Human DNAJ in cancer and stem cells

Cancer Letters 312 (2011) 129–142

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Mini-review

Human DNAJ in cancer and stem cells Jason N. Sterrenberg, Gregory L. Blatch, Adrienne L. Edkins ⇑ Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown 6140, South Africa

a r t i c l e

i n f o

Article history: Received 23 March 2011 Received in revised form 15 July 2011 Accepted 17 August 2011

Keywords: DNAJ HSP40 Cancer Stem cell Cancer stem cell Chaperone

a b s t r a c t The heat shock protein 40 kDa (HSP40/DNAJ) co-chaperones constitute the largest and most diverse sub-group of the heat shock protein (HSP) family. DNAJ are widely accepted as regulators of HSP70 function, but also have roles as co-chaperones for the HSP90 chaperone machine, and a growing number of biological functions that may be independent of either of these chaperones. The DNAJ proteins are differentially expressed in human tissues and demonstrate the capacity to function to both promote and suppress cancer development by acting as chaperones for tumour suppressors or oncoproteins. We review the current literature on the function and expression of DNAJ in cancer, stem cells and cancer stem cells. Combining data from gene expression, proteomics and studies in other systems, we propose that DNAJ will be key regulators of cancer, stem cell and possibly cancer stem cell function. The diversity of DNAJ and their assorted roles in a range of biological functions means that selected DNAJ, provided there is limited redundancy and that a specific link to malignancy can be established, may yet provide an attractive target for specific and selective drug design for the development of anti-cancer treatments. Ó 2011 Elsevier Ireland Ltd. All rights reserved.

1. Molecular chaperones and co-chaperones Molecular chaperones are the guardians of protein homeostasis in the cell. These proteins participate in several key cellular functions under both physiological and stressful conditions, including the suppression of protein aggregation, assisting the folding of nascent and damaged proteins, translocation of proteins into cellular compartments and the targeting of proteins for degradation [1–3]. The largest and most well-described group of molecular chaperones are the heat shock proteins (HSP), a term that was coined at the discovery of the expression of these genes in heat treated cells [4]. Not all HSP are stress inducible; many are constitutively expressed and have house-keeping functions within the cell [5]. There are several HSP classes that function as molecular chaperones, including the well-characterised HSP90 (HSPC) and HSP70 families

⇑ Corresponding author. Tel.: +27 46 6038446; fax: +27 (0)865461893. E-mail address: [email protected] (A.L. Edkins). 0304-3835/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2011.08.019

(HSPA), and the less-well studied HSP40 group (DNAJ) which contains the greatest number of members [6,7]. The original HSP nomenclature was derived from the approximate molecular sizes of the HSP, for example HSP90 isoforms have a molecular weight of approximately 90 kDa, while HSP70 isoforms are approximately 70 kDa in size [1,2]. Molecular chaperones facilitate the folding of polypeptides in the crowded cellular environment but do not constitute part of the final protein product. Chaperones facilitate protein folding; the information required for the protein to assume its correct three-dimensional structure is contained within the primary amino acid sequences of the polypeptide in question [8–10]. However, most chaperones, including members of the HSP70 and HSP90 family, also participate in the regulation of protein conformation and stability, protein transport and protein–protein interactions in addition to protein folding [11,12]. The functional importance of molecular chaperones together with their implications in disease states has identified chaperones as key drug targets in cancer, none more so than HSP90. More recently, focus has shifted towards the targeting of other

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components of the chaperone machinery as drug targets in cancer, with both HSP70 [13,14] and the heat shock transcription factor HSF-1 [15] being considered as potential drug targets for cancer. As most chaperones do not function alone but rather as part of multi-protein complexes consisting of other chaperones, in addition to chaperone-regulating proteins known as co-chaperones [16,17]. Co-chaperones modulate chaperone function, either by stimulation of the chaperone [by co-chaperones such as DNAJ and p23] [18,19], or by the recruitment of other chaperones [by co-chaperones such as the Hsp70–Hsp90 organising protein (HOP)] into active multi-chaperone complexes [20]. Through these mechanisms, co-chaperones are key regulators of chaperone function. However, relatively little attention has been focused on the potential of co-chaperones as drug targets. We describe the expression and function of the largest and most diverse family of cochaperones, the DNAJ proteins, in cancer and illustrate how the different isoforms regulate the activity of the major chaperone drug targets, HSP90 and HSP70. Although most DNAJ cannot be classified as true tumour suppressors or oncogenes, many of the client proteins chaperoned by DNAJ are bona-fide tumour suppressors or oncoproteins [21] which are also considered drug targets. Hence, DNAJ could be regarded as potential ‘‘drug targets that chaperone other drug targets’’. The activities of the DNAJ proteins may mean that these proteins could be more specific and selective drug targets than HSP70 and HSP90.

2. DNAJ: diversity of structure, function and expression The largest and most diverse family of co-chaperones is the DNAJ family of proteins. The DNAJ family in humans currently consists of 49 members and is divided into three subclasses, type I (DNAJA), type II (DNAJB) and type III (DNAJC), based on the presence or absence of conserved domains defined by the canonical Escherichia coli DNAJ, DnaJ (Fig. 1A) [6,22]. Type I DNAJ (DNAJA, 4 members) consist of an N-terminal J-domain, a glycine/phenylalanine (G/F) rich region, a cysteine repeat (Cys-repeat) region and a largely uncharacterized C-terminus, while type II DNAJ (DNAJB, 13 members) lack the Cys-repeat region and have an extended G/F rich region. Type III DNAJ (DNAJC, 32 members) differ substantially from type I and type II DNAJ as they lack the G/F and Cys-repeat regions and the J-domain may be situated anywhere along the protein [5,6,22]. Type I DNAJ display the greatest domain similarity across the subclasses. Domain similarity is also evident, although to a lesser extent, in the type II subclass in which certain members contain some non-classical domains, such as the ubiquitin-interacting motifs (UIMs) of DNAJB2 for example. DNAJB2 (otherwise known as HSJ1) is a neuronal chaperone involved in proteosomal degradation of client proteins aided by its J-domain and UIMs which interact with ubiquitinated clients providing specificity for clients entering the proteosomal degradation process [23,24]. Type III DNAJ, by contrast, are highly divergent in both molecular weight and domain architecture, with the J-domain being the only conserved domain within all members of the subclass. Many of the type III DNAJ possess other specialised domains not normally associated with DNAJ function. With

the discovery of novel DNAJ members and the identification and characterisation of these non-classical domains in many DNAJ isoforms, the classification by comparison toE. coli DnaJ may be simplistic and therefore could be readdressed to avoid possible ambiguity (reviewed in [25]). Furthermore, the HSP40 terminology denotes that these proteins have an approximate molecular weight of 40 kDa, despite the fact that the large majority of DNAJ members have a molecular weight that is either far less or far greater. The presence of the highly conserved 70 amino acid J-domain, highly conserved across all organisms, is considered the defining characteristic of all DNAJ proteins [18,22]. The J-domain is pivotal for the interaction with, and stimulation, of the molecular chaperone HSP70 [18,26–29]. The structure of the J-domain comprises four a-helices that interact to provide the correct orientation for the J-domain to perform its co-chaperone function of stimulating the ATPase domain of HSP70. Helix 2 and 3 are antiparallel and are positioned such that they mimic a protruding ‘finger’, while helix 1 and 4 are positioned to stabilize helix 2 and 3. Located on the loop between helix 2 and 3 (at the tip of the ‘finger’) is the highly conserved histidine–proline–aspartic acid [HPD] motif that is essential for the stimulation of ATP hydrolysis of HSP70 (Fig. 1B). The G/F rich region is also thought to make contact with HSP70 and support the interaction between the J-domain and the ATPase domain of HSP70 to promote the formation of a stable chaperone complex [30,31]. The G/F rich region, however, is not necessary for stimulation of HSP70, as indicated by the fact that selected type III DNAJ (DNAJC) can stimulate ATP hydrolysis independently of the G/F rich region [32], as can the isolated J domain of E. coli DnaJ [33–35]. The Cys-repeat region, also known as the Zinc finger, consists of the motif Cys-X-X-Cys repeated four times, where X represents any amino acid. This region forms part of the DNAJ substrate binding domain that is important for the presentation of peptides to HSP70 [36,37]. In this way, DNAJ may regulate the specificity of HSP70 action on different client substrates, particularly since there are 49 DNAJ and only 13 HSP70s [5,7,25]. It is thought that type I and II DNAJ have a relaxed client substrate specificity as the G/F rich region ensures the correct positioning of the J-domain for interaction with the HSP70 ATPase domain, while type III DNAJ have a more stringent client substrate specificity such that client binding correctly positions the J-domain for interaction with HSP70 ATPase domain [22,38]. The C-terminal region of the DNAJ family remains largely uncharacterized, although this region is understood to contain the substrate binding domain of type I and II DNAJ, and is crucial for efficient co-chaperone functioning [39–41]. As such, the role of any non-classical DNAJ domains contained within this region may be critical for the specificity of function of the co-chaperone, particularly in the case of type III DNAJ members.

3. DNAJ as co-chaperones for HSP70 The canonical co-chaperone roles for DNAJ are the presentation of client peptide substrates to the HSP70

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Fig. 1. Classification and functional domains of DNAJ. (A) Classification of DNAJ proteins into three families according to Cheetham and Caplan [22]. DNAJ may be classified according to the presence or absence of three domains, namely the J domain, a glycine/phenylalanine rich region (G/F) and the cysteine repeat motif (Cys-repeats) together with a C terminal domain that is largely uncharacterized. (B) The three dimensional J-domain structure (E. coli J-domain; 1BQ0) that is currently used to define the DNAJ family. The figure illustrates the structure of the J domain that resembles a ‘protruding finger’ (helix 2 and 3) containing the highly conserved HPD (His–Pro–Asp) motif located on the loop between helix 2 and 3. This HPD motif is important for stimulation of Hsp70 ATPase activity. The figure was rendered using Pymol [DeLano Scientific].

chaperone and stimulation of HSP70 ATP hydrolysis [5,42– 44]. HSP70 chaperone function is cyclical in nature and regulated in an ATP and DNAJ-dependent manner. HSP70, when bound to ATP via the N-terminal ATPase domain, has a low affinity for client binding. The interaction between the highly conserved HPD motif of the J-domain and the ATPase domain of HSP70 is important for the stimulation of HSP70 ATPase activity by DNAJ. ATP hydrolysis to ADP increases the affinity of HSP70 for the client polypeptide, and hence promotes the formation of a stable HSP70-client complex [5,18,22,26]. Therefore the interaction between HSP70 and DNAJ is important for the stabilization of the HSP70-client complex, although the binding of HSP70 alone is sufficient to activate HSP90 ATPase activity and increase the affinity of HSP70 for its client protein. As such canonical DNAJ may function to both deliver client proteins to HSP70 and to regulate the affinity

of HSP70 for those clients through the stimulation of ATPase activity (Fig. 2). There is evidence of specific partnerships between certain DNAJ proteins and specific HSP70 members that may be of functional relevance [29]. Evidence from J-domain swapping experiments suggests that specific DNAJ–HSP70 partnerships are apparent between co-localised DNAJ and HSP70 members in different subcellular locations within the cell. Specificity exists at the level of the J-domain as DNAJ members may only be able to interact with specific HSP70 members in a J-domain-dependent manner. For example, only the J-domains from endoplasmic reticulum (ER) localised DNAJ are able to bind and efficiently stimulate ER-localised HSP70 [28,29]). Therefore the DNAJ–HSP70 machine displays multiple layers of specificity. The expression of specific DNAJ members determines the specificity of clients that will enter the HSP70 pathway. Specificity may also be

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Fig. 2. Proposed model of chaperone-assisted protein folding by the HSP70–DNAJ complex. Although HSP70 also functions in the regulation of protein transport, degradation and protein–protein interactions, one of the best described roles for the HSP70 chaperone is in the folding of nascent or denatured polypeptides, in cycles that are controlled by ATP and the association with DNAJ co-chaperones. (1) DNAJ forms a transient association with the unfolded protein (substrate) via exposed hydrophobic residues for delivery of the substrate to HSP70. (2) DNAJ binds to the ATP-bound form of HSP70, and transfers the misfolded or unfolded protein to the substrate binding cleft of HSP70. DNAJ stimulates the hydrolysis of ATP to ADP by the ATPase domain of HSP70. The ADP-bound form of HSP70 has a higher affinity for the protein substrate than the ATP bound form, and thus binds tightly to the unfolded protein and DNAJ leaves the complex. (3) Unfolded protein is prevented from aggregation or non-productive folding pathways. (4) The ATP-bound form of HSP70 is regenerated by the activity of nucleotide exchange factors (such as BAG1). ATP bound Hsp70/DnaK has a lower affinity for the substrate and so the protein is released, to fold to its normal conformation or re-associate with another chaperone. The chaperones and co-chaperones are now able to continue the chaperone-assisted protein folding cycle [9,25,159,160].

regulated by subcellular location, where different subcellular locations of DNAJ may influence biological function and client specificity. Client substrate binding is specific, DNAJ members will only bind to specific client substrates [particularly with respect to type III DNAJ members] and present them to HSP70. Certain DNAJ (particularly members of the type II DNAJB subclass) may also possess chaperone-like activities, such as the ability to suppress the aggregation of client proteins (DNAJA1A, DNAJB1, DNAJB6b and DNAJB8) independently of HSP70 chaperones [45,46]. Some type III DNAJ, are thought not to interact with chaperone clients but rather use the J domain to recruit HSP70 to a specific subcellular location for a discrete function. These DNAJ often consist of the J-domain in conjunction with multiple other non-classical DNAJ functional domains, including transmembrane domains [25]. The varied arrangement and presence of ‘non-classical’ DNAJ domains indicate that the majority of type III DNAJ may have functions other

than HSP70 stimulation, and as such the cellular importance of this class of proteins is currently underestimated. The requirement for a functional J domain in all DNAJ has been challenged by the recent identification of DNAJ isoforms whose functions are apparently independent of the J domain. The type III DNAJ, CWC23, absence of which is lethal to cells [47], contains a putative spliceosome binding site and RNA recognition motif located at the C-terminus that is essential for the interaction with Ntr1, a protein involved in spliceosome disassembly. The J-domain was not necessary for CWC23 functioning; in this context the J domain appears to be an auxiliary domain, only required when interaction with Ntr1 is compromised [48]. Similarly, DNAJB6b and DNAJ8 are capable of J-domain independent aggregation suppression of polyglutamine containing proteins [46], and the J domain of the functional DNAJB13 isoform in humans lacks the HPD motif required for the stimulation of HSP70. It is possible that these proteins contain J-domains that have become redundant due to the

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acquisition and evolution of non-classical DNAJ domains, which have superseded the functional and biological importance of the J-domain; or that the J domain function in these proteins is only required when the activity of the alternative domain is compromised [25]. There is some evidence that shows that the entire J-domain is encoded by a single exon in some DNAJ genes and therefore suggests that this domain could have been incorporated into proteins by exon shuffling [49,50] to provide such a compensatory mechanism for activity under irregular conditions.

4. DNAJ as indirect regulators of the HSP90 multichaperone complex The HSP90 family of molecular chaperones function to exclusively mediate the folding and stability of numerous transcription factors and signalling intermediates in vivo. In eukaryotic cells, the cytoplasmic Hsp90 species are one of the most abundant cellular molecular chaperones. HSP90 regulates the conformational stability of client proteins via a mechanism dependent on ATP hydrolysis and association with other chaperones and co-chaperones into a functional complex. Studies on progesterone receptor (PR) maturation, perceived as the model client for studying the HSP90 multi-chaperone complex, revealed a minimum set of five proteins required for maturation of PR, including DNAJ and HSP70 [51,52]. DNAJ binding to the client was not only shown to be the first step in the maturation of PR, but it was the only element that did not require other proteins or cofactors to be bound [51–53]. It is likely therefore that the importance of DNAJ in the HSP90 multi-chaperone mechanism holds true for other, if not all, HSP90 clients that undergo maturation through the multi-chaperone complex; although the modulation of HSP90 function by DNAJ is likely to be indirect and mediated by DNAJregulated changes in the activity of HSP70, as opposed to direct interactions between DNAJ and HSP90 [54,55]. The DNAJ studied in PR maturation studies was the type I HDJ2 (DNAJA1) although HDJ1, a type II DNAJ (DNAJB1), has also been shown to be capable of PR maturation. As one might expect, the different DNAJ displayed different binding characteristics [53]. HDJ1 has additionally been found to be the first step required for the formation of an HSP90 multichaperone complex with mutant p53, an HSP90 client that is mutated in over 50% of cancers [21,56]. In the study, HDJ1 displayed a greater affinity for mutant p53 compared to wild type p53, resulting in the stabilization of the p53-HSP90 complex which prevented the ubiquitin-mediated degradation of mutant p53 [56,57]. Mutations in p53 can result in gain of function, such as transactivation of genes including c-Myc [58]. Recently, mutant p53 was found to enhance the metastatic potential of cancer cells through integrin cycling and alteration of Akt signalling [59], implicating a potential role for DNAJ in the HSP90-mediated development and spread of cancer. It is plausible that different HSP90 clients will have different DNAJ requirements based on DNAJ client binding specificities, as reflected by the ability of HDJ1 and HDJ2 to both promote PR maturation by HSP90, while HDJ1 is more efficient in the maturation of checkpoint kinase 1 (Chk1) than HDJ2 [54]. Therefore DNAJ,

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in determining the client specificity for HSP70s, may in turn indirectly influence the client proteins entering the HSP90 chaperone complex. DNAJ that do interact directly with HSP90 may offer an alternative means of directly targeting HSP90 function [54,55,60]. Currently there are only two DNAJ, DNAJC7 (Tpr2 [61,62]) and, DNAJB2 isoform b (HSJ1b [63]) and that have been established as interacting directly with HSP90. DNAJC7 contains multiple copies of the highly conserved tetratricopeptide repeat (TPR) motif [64] that is found in other co-chaperones that bind both HSP90 and HSP70, such as HOP (HSP90–HSP70 organising protein) [65,66]. HOP plays an integral role in modulating the transfer of clients from HSP70 to HSP90 [67,68] with the TPR motifs crucial for interaction with both Hsp70 and HSP90 [20,65]. TPR-containing proteins typically interact with HSP70 and HSP90 via the C-terminal EEVD motif of these chaperones [65]. The ER resident DNAJC3 (P58IPK) also contains TPR motifs and therefore is predicted to associate with HSP90 and/or HSP70 via these domains. Although an interaction between HSP90 and DJANC3 remains to be demonstrated experimentally, this observation is interesting in the context of the fact that some of the published activities of DNAJC3 appear to be independent of the J domain [69,70]. The localisation of TPR containing DNAJ chaperones in the ER is also interesting from a mechanistic point of view, as the ER homologues of Hsp70 and Hsp90 lack the C-terminal EEVD motif [71]. There is some evidence from r structural studies on DNAJC3 that suggest that the TPR domains of ER resident DNAJ may not be involved in HSP90 or HSP70 binding, but may be recruited for an alternative purpose, such as client protein binding [72].

5. Cancer-associated DNAJ HSP90 and HSP70 have already been established as important factors in cancer and are regarded as bona fide anti-cancer drug targets. In contrast to the data on HSP70 and HSP90, there is limited information available on the expression and function of most DNAJ in cancer. It is however evident from specific DNAJ that have been identified (Table 1), that these proteins may play an important role in influencing cancer properties. In many cases, DNAJ isoforms may contribute towards the development and spread of cancer through their role as co-chaperones for various oncogenes or tumour suppressors [73,74]. Malignant cells are perceived as being under stress and undergoing rapid proliferation, both of which are synonymous with chaperone over-expression, particularly HSP90 and HSP70 [75,76]. As such it is highly likely that selected DNAJ, functioning to regulate HSP70 and the HSP90 multi-chaperone complex and to chaperone client proteins involved in oncogenesis, will be over-expressed. The regulatory roles and client specificities of DNAJ imply that the state of expression of specific DNAJ within cells is important to promote or negate the function of specific clients, clients potentially involved in either cancer progression or tumour suppression. It is worth noting that although there are approximately 49 genes encoding DNAJ, several of these genes encode for multiple splice variants that may have opposing biological

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Table 1 Human DNAJ isoforms implicated in cancer development and metastasis. DNAJ

Alternative name

Malignant tissue

Function

Reference

DNAJA1

HDJ2

Expression correlated with malignancy and resistance to radiotherapy

[115,161]

DNAJA3

TID-1

Glioblastoma Prostate Osteosarcoma

NF-jB signalling regulation [apoptosis and migration/metastasis regulation], regulation of c-Met tyrosine kinase signalling [regulation of cell migration] and inhibition of oncogenic STAT5b [cell growth regulation]

[77,84–88,162]

DNAJB4

HLJ1

Melanoma Breast Kidney Haematopoietic Lung

[94,100,103]

DNAJB6

MRJ

Breast

DNAJB11

ERDJ3

DNAJC9 DNAJC10 DNAJC15

JDD1, DJC9 ERDJ5 MCJ

KSHV-related tumours Ovarian Cervical Neuroblastoma Ovarian

Expression inhibits proliferation, anchorage-independent growth, tumorigenesis, motility and invasion and promotes apoptosis Inhibits migration, invasion and tumorigenesis through inhibition of Wnt signalling pathway Expression required for KSHV-induced cellular transformation and inhibition of apoptosis Expression upregulated in paclitaxel resistant ovarian cancer Expression upregulated in metastatic versus non-metastatic tumours Over-expression sensitises cells to ER-stress induced apoptosis Expression associated with enhanced drug sensitivity through decreased expression of ABCB1 Expression inactivated by methylation in malignant paediatric brain tumours

Brain

[78,91] [163,164]

[155] [133] [104,105,107,165,166]

Abbreviations: KSHV: Kaposi’s sarcoma – associated herpesvirus; STAT5b: signal transducer and activator of transcription 5b; ER: endoplasmic reticulum; NF-jB : nuclear factor kappa B.

functions (e.g. DNAJA3 isoforms [77]) and cellular locations (e.g. DNAJB6 isoforms [78]). As such, there are likely to be more than 49 functioning DNAJ, with the potential for different biological impact depending on the context and isoform expressed. Many splice variants, including DNAJA3, DNAJB2 and DNAJB6, display a common variation in that they possess a truncated C-terminus, believed to be the putative DNAJ client binding domain for type I and II DNAJ [25]. In the case of DNAJB6, the C-terminal truncation of the smaller isoform results in the loss of a nuclear localisation signal (NLS), resulting in DNAJB6 isoforms with different subcellular localisations. In the case of DNAJC19 the N-terminal truncated isoform lacked both a signal peptide and a transmembrane domain that was present in the other isoform. The subcellular localisation of the DNAJ may influence the functional importance of the different domains of that isoform. For example, P58IPK [DNAJC3] comprises an N-terminal ER signal sequence, eight tetratricopeptide repeats [TPR] and a C-terminal J-domain. Although predominantly localised to the ER, P58IPK was also found in the cytoplasm, where it displayed both unique function and client specificity. In the cytoplasm, P58IPK inhibited the kinases PKR and PERK independently of its J-domain [69,70], while in the ER it selectively presented misfolded and unfolded clients to the ER HSP70 (BiP) and stimulated HSP70 functioning in a J-domain dependent fashion [79,80]. 5.1. DNAJ associated with both pro- and anti-cancer properties TID1 (DNAJA3) is the human homologue of the Drosophila tumour suppressor l[2]TID, which is currently the only DNAJ-like protein recognised as a true tumour suppressor [81]. Two mRNA splice variants of TID1 that display opposing functions with respect to apoptosis have been identified.

The difference between the TID1-L (large isoform; 43 kDa) and TID1-S (small isoform; 40 kDa) is the truncated C-terminus of TID1-S. The TID1-S protein has the last 33 C-terminal amino acids of TID1-L replaced by a unique six amino acid sequence [77], a truncation similar to that observed in DNAJB6 isoforms. Both TID1 isoforms are predominantly localised to the mitochondrial matrix, where they interact specifically with the mitochondrial HSP70 (GRP75; HSPA9). TID1-L over-expression increased apoptosis levels in U20S osteosarcoma cells upon treatment with mitomycin C and tumour necrosis factor a (TNFa), while TID1-S over-expression decreased apoptosis levels with the same treatments [77]. This result was confirmed for TID1-L whereby knockdown of this splice variant decreased apoptosis levels during apoptosis-promoting treatments in both U20S and HeLa cells [82]. This dual function may be explained by the differential regulation of the NF-jB pathway by the different TID1 isoforms [83–85]. TID1-L suppresses NF-jB signalling through repression of IjK activity and stabilisation of IjB [84]. Depletion of both isoforms of TID1 increases in vitro migration and in vivo metastasis of MB-MDA-231 cells, resulting from the upregulation of IL-8, an NF-jB target gene, through stimulation of NF-jB signalling [85]. Over-expression of TID1-L was shown to induce growth arrest and cell death in U20S cells in a J-domain dependent manner [84]. This was not the case in MB-MDA-231 breast carcinoma cells, where abrogation of both TID1 isoforms had no effect on growth under normal conditions [85,86]. Differences in the TID1-mediated growth arrest and cell death appeared to be dependent on the ErbB-2 [Her2] expression status of cells. Over-expression of TID1 in ErbB-2 over-expressing breast carcinoma cell lines was found to inhibit proliferation and induce cell death, while this effect was not observed in ErbB-2 low expressing cell lines. TID1 expression promotes the ubiquitination and hence degradation of ErbB-2, which results in the inhibition

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of several important signalling pathways including the MAPK pathway, resulting in the induction of programmed cell death [86]. More recently TID has been shown to bind to and regulate signalling from the c-Met receptor tyrosine kinase (MetR) in renal cell carcinoma. Expression of TID-S isoform enhanced cell migration but did not induce cell proliferation, while knockdown of TID decreased migration through the reduction of phosphorylation of MetR and inhibition of ERK and STAT3 signalling [87]. TID has also been shown to bind directly to STAT5b but not STAT5a in haematopoietic cells. In this context, TID prevents the expression and transcriptional activation of the oncogenic STAT5b [88]. In the case of both STAT5b and MetR, the authors describe the role of h-TID as a physical association between this DNAJ and the client protein. These associations might suggest that h-TID is acting as a chaperone in its own right, to regulate the conformation and stability of these clients, a function normally reserved for chaperones such as HSP90 and HSP70. It remains to be determined whether the regulation of STAT5b and MetR by h-TID involves these other chaperone pathways. Mammalian relative of DnaJ (MRJ), a DNAJ highly enriched in the central nervous system [89], is a type II DNAJ-like protein (DNAJB6) that has been found to negatively affect breast cancer properties [78]. Similar to TID1, there are two isoforms of MRJ. MRJ-S is the smaller isoform, in which the last 95 amino acid C-terminus of MRJ-L is replaced by a unique 10 amino acid sequence. MRJ-S was exclusively located in the cytoplasm, while the larger isoform, MRJ-L, localised to both the cytoplasm and the nucleus as a result of a nuclear localisation signal (NLS) located in the C-terminus [90]. Breast cancer cell lines were found to display very low mRNA and protein levels of MRJ-L, with the exception of the MB-MDA-231 cell line. By contrast, MRJ-S was detectable in all cell lines with no significant differential expression levels between cell lines [78]. Over-expression of MRJ-L resulted in decreased migration and anchorage-independent growth properties of the breast cancer cell lines [78], while constitutive over-expression of MRJ-L induced the loss of mesenchymal markers, most notably b-catenin, and promoted the acquisition of epithelial markers, such as Keratin 18, known to associate with MRJ [91,92]. The effect of MRJ-L was mediated through inhibition of the Wnt/b-catenin signalling pathway. MRJ-L expression was associated with the upregulation of DKK1, an inhibitor of the Wnt/b-catenin pathway that blocks the Wnt co-receptor Lrp5/6 resulting in the phosphorylation and proteosomal degradation of b-catenin [93]. The inhibition of DKK1 in MRJ-L over-expressing cells abrogated Wnt/b-catenin signalling [91]. Whether or not the effects of MRJ are as a result of a co-chaperone interaction with HSP70 or HSP90 remains to be determined, although a recent study has reported that both isoforms of DNAJB6 were functional in chaperone aggregation suppression assays [46]. DNAJB6a (nuclear) was able to suppress aggregation of nuclear-targeted, but not cytosolic, polyglutamine proteins, while DNAJB6b (cytosolic and nuclear) was capable of suppression of aggregation of the cytosolic polyglutamine protein, which suggests that compartmentalisation may influence the function of DNAJ isoforms [46].

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5.2. DNAJ associated with anti-cancer properties Research on non-small-cell lung carcinoma (NSCLC) cell lines with differing invasion properties identified a negative correlation between HLJ1 (DNAJB4) expression and invasive properties [94,95]. HLJ1 was upregulated in less invasive cell lines compared to the highly invasive cell lines and overexpression of HLJ1 reduced numerous malignant properties including invasion, migration, anchorage-independent growth and in vivo tumour growth rate. Samples taken from primary tumours and the adjacent normal lung tissue showed that HLJ1 was less abundant in the tumour tissue compared to the normal tissue samples [94]. HLJ1 expression appeared to affect the expression of several genes and most notably suppressed the expression of CD44, a cell surface adhesion molecule that is a putative marker of cancer stem cell (CSC) populations from numerous malignant tissues [96–99]. HLJ1 expression correlated with reduced cancer recurrence in patients. The anti-cancer properties of HLJ1 in NSCLC are thought to result in part from the activation of STAT1 and p21WAF1 pathways that inhibit cell cycle progression [94]. HJL1 expression potentiates UV-induced apoptosis as a substrate of caspase-3 [100], while treatment of NSCLC cells with the anti-cancer agent curcumin reduced the metastatic potential of cells through induction of HLJ1 expression [101,102]. This may be as a result of HLJ1 directly modulating cell migration, as tyrosine phosphorylation of HLJ1 under conditions of acidic stress leads to a direct association of phospho-HLJ1 with the actin cytoskeleton [103]. Silencing of the DNAJ MCJ (DNAJC15) through hypermethylation appears to be a tumour specific event in early childhood brain tumours. As MCJ expression is regulated by methylation this might suggest a link with inherited epigenetic risk factors for tumour development [104]. Low levels of MCJ correlated with increased resistance to chemotherapy in ovarian cancers in vitro [105], which is corroborated by results from in vivo studies. In clinical treatment of ovarian cancer patients, those with high levels of MCJ promoter methylation (and consequently low MCJ expression) were correlated with poor prognosis and resistance to chemotherapy [106]. This may be due to the upregulation of expression of drug transporters, such as ABCB1 (MDRP1; multi drug resistance protein 1) by MCJ downregulation [107]. 5.3. DNAJ associated with pro-cancer properties JDP1 (DNAJC12) was differentially expressed between oestrogen-receptor negative (ER ) and oestrogen-receptor positive (ER+) breast cancers with expression being significantly higher in ER+ breast tumours [108,109]. The JDP1 promoter contains oestrogen response elements (EREs) which are recognised by oestrogen–oestrogen receptor (oestrogen-ER) complexes. The binding of oestrogen-ER complexes to EREs located in the promoters of certain genes induces expression of these genes. Therefore stimulation of ER leads to expression of JDP1. This involvement suggests that JDP1 may play a role in the HSP90 pathway which maintains the integrity and functionality of ER in mammary gland and breast tumour tissues [109], as well

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as a potential role in regulating the function and correct folding of genes targeted by ER signalling. DNAC12 and DNAJC10 were also upregulated at the RNA level in ER+ cultures of breast cancer stem cells [110]. ERDJ5 (DNAJC10) is involved in maintaining endoplasmic reticulum homeostasis by promoting endoplasmic reticulum-associated degradation of misfolded proteins. Neuroblastoma cells over-expressing ERDJ5 were found to be more susceptible to endoplasmic reticulum stress-induced apoptosis as a result of ERDJ5 inhibiting the endoplasmic reticulum stress-induced survival mechanism in a J-domain dependent manner, thereby promoting ER stress-induced apoptosis [111]. Another ER-resident DNAJ that has a role in cancer is ERDJ3 (DNAJB11). Expression of this type II DNAJ has been linked with resistance to paclitaxel in ovarian tumours and is required for expression of the K1 protein from Kaposi’s sarcoma herpesvirus (KSHV) and for K1-induced cellular transformation and prevention of apoptosis. KSHV infection is associated with three types of malignancy, Kaposi’s sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman disease, and is the most common cancer of HIV infected individuals. ERDJ3 facilitates cancer development because it is essential for the expression of viral proteins. This is an interesting fact when you consider that in many cases, oncogenic viruses often require specific DNAJ for tumourigenicity. For example, HSJ3 (DNAJC14) is required for replication of Flaviviridae, including HCV (hepatitis C virus) which causes heptocellular carcinoma [112]. Similarly, the viral origin J domain-containing SV40 tumour antigen is required for cellular transformation [113] and cooperates with the human DNAJ HDJ2 (DNAJA1A) [114]. While an in depth description of the role of DNAJ as chaperones for viral proteins is beyond the scope of this review (described recently in [115]), it is clear that selected DNAJ may also contribute indirectly to tumourigenicity by acting as chaperones for viral oncoproteins. HDJ2 (DNAJA1) expression has also been linked with oncogenesis and resistance to radiotherapy in glioblastoma. Over-expression of HDJ2 led to radiation-resistant tumours, while inhibition of HDJ2 rendered tumours sensitive to radiotherapy [116].

6. Stem cell associated DNAJ Stem cell-associated DNAJ are of interest to cancer research due to the link between the activation of stem cell signalling pathways and malignancy [117–119]. The chaperone expression profile, and in particular that of DNAJ, is relatively unknown in human stem cells due to the legislative and technical challenges associated with stem cell research. However, an extensive proteomics study on human embryonic stem cells (hESC) has revealed several DNAJ, including two type I (DNAJA1 and DNAJA2) and three type III (DNAJC7, DNAJC8 and DNAJC9) DNAJ, as being abundant in hESC at the protein level [120]. Rat DNAJ protein JDD1, which shares 84% identity and 90% similarity with DNAJC9 and is therefore presumed to be the rat homologue of human DNAJC9, is expressed in the germinal zone of the rat nervous system during middle stage rat

embryogenesis and persist throughout adulthood suggesting a potential role in neural development. JDD1 is expressed in the lung and liver during rat embryogenesis [121]. MRJ (DNAJB6) is the most abundant DNAJ in embryonic stem cell tissues and has been found to play a vital role in early embryogenesis in mice where it is highly expressed in the placenta and is critical for placental development [122]. Similarly, MRJ has been found to play an important role in murine neuronal stem cell self-renewal. Using sphere formation in anchorage-independent in vitro conditions as a sign of self-renewal, it was shown that MRJ-negative neural cells formed neurospheres at a lower frequency with reduced area, and gave rise to fewer secondary spheres, signifying a role for MRJ in stem cell self-renewal [123]. MRJ has also been found to play an important role in T-cell quiescence through its interaction with Schlafen1, a cyclin D1 inhibitor that is preferentially expressed in T-cells. The interaction between MRJ and Schlafen1 allows Schlafen1 to enter the nucleus in a MRJ nuclear localisation-dependent manner whereby the entire MRJ-Schlafen1 complex enters the nucleus [90]. Given the opposing roles of the different isoforms of DNAJB6 in cancer development, in particular the ability of the large isoform of DNAJB6 to inhibit the stem cell-associated Wnt signalling pathway in cancer cells [78], it would be interesting to identify which isoform of DNAJB6, if any, was preferentially expressed in stem cells. The cancer stem cell hypothesis describes cancer development and maintenance as being driven by cancer cells that display stem-like properties (reviewed in [124,125]), which like normal tissue stem cells, are capable of both self-renewal and differentiation. These cells are thought to be exclusively responsible for tumorigenesis (tumour development) just as normal tissue stem cells are required for organogenesis (organ development) [126,127]. Recent gene expression analyses have described the differential expression of a number of DNAJ in cancer stem cell populations from breast cancer. DNAJA1, DNAJB1, DNAJC9, DNAJC10, DNAJC12 were all upregulated in cancer stem cell populations relative to normal cell populations, while DNAJC12 and DNAJB2 were downregulated [110,128–130]. Interestingly, a different expression profile for DNAJC11 was noted between two studies; in the one case, DNAJC11 was downregulated [131,132]), while in the other DNAJC11 was upregulated [130]. Of the DNAJ identified in cancer stem cell populations, it is of interest that DNAJA1 and DNAJC9 were also upregulated at the protein level in human embryonic stem cells [120], while DNAJA1 expression was linked with malignancy and resistance to radiotherapy in glioblastoma [116] and DNAJC10 expression sensitised neuroblastoma cells to apoptosis [133]. However, care must be taken in the interpretation of these results as they represent data from a limited number of gene expression profiling studies. Cancer stem cells are rare cells (<0.1% of the tumour bulk) and hence microarray analysis is often the best option for the analysis of gene expression in these samples. Although this approach is useful in identifying possible target genes for anti-cancer therapies, high mRNA expression levels in tissues do not necessarily correlate with protein expression levels nor do they infer a causal relationship between the

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J.N. Sterrenberg et al. / Cancer Letters 312 (2011) 129–142 Table 2 DNAJ isoforms identified in stem and cancer stem cells. DNAJ

Alternative name

Tissue

RNA/protein

Expression status

Method

Reference

DNAJA1

DJ2

DNAJA2 DNAJB1 DNAJB2 DNAJC7 DNAJC8 DNAJC9

DJ3 HSPF1; Hsp40 HSJ1 TTC2; TPR2 spf31 JDD1, DJC9

DNAJC10 DNAJC12 DNAJC13 DNAJC19

ERDJ5 JDP1 RME8 TIM14

CD44+ BC Tumoursphere BCSC hESC hESC CD44+/CD24 BCSC Tumoursphere BCSC hESC hESC Tumoursphere BCSC hESC ER+ Tumoursphere BCSC ER+ Tumoursphere BCSC CD44+/CD24 BCSC ALDH+ BCSC

RNA RNA Protein Protein RNA RNA Protein Protein RNA Protein RNA RNA RNA RNA

Upregulated Upregulated Upregulated Upregulated Differential Downregulated Upregulated Upregulated Upregulated Upregulated Upregulated Upregulated Differential Downregulated

SAGE Microarray FT-ICR-MS/MS FT-ICR-MS/MS Microarray Microarray FT-ICR-MS/MS FT-ICR-MS/MS Microarray FT-ICR-MS/MS Microarray Microarray Microarray Microarray

[128] [130] [120] [120] [129]a [130] [120] [120] [130] [120] [110] [110] [129]a [132]

BC = breast cancer; SAGE = serial analysis of gene expression; BCSC = breast cancer stem; cells; hESC = human embryonic stem cells; FT-ICR-MS/ MS = Fourier-transform ion cyclotron resonance mass spectrometry. a Comparison for differential expression made between BCSC and normal breast cancer tissue.

gene and disease. Further research will be essential to establish a causative link between the differential DNAJ expression and the cancer stem cell phenotype.

7. DNAJ: a future chaperone cancer drug target? Many molecular chaperones, in particular HSP90, are considered bona fide drug targets for anti-cancer therapies. Inhibitors of HSP90, such as 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), a synthetic analogue of the naturally occurring HSP90 inhibitor geldanamycin (GA), are currently undergoing clinical trials for effectiveness as anti-cancer drugs. In tumour cells, HSP90 is thought to exist in an activated conformation that displays a higher affinity for HSP90 inhibitors such as GA and 17-AAG compared to HSP90 in non-malignant cells [134]. This higher order complex is thought to contribute towards the fact that HSP90 can be selectively targeted in tumour cells [135]. This finding, together with the fact that several HSP90 clients are oncogenes (reviewed in [136]), has made HSP90 a target for anti-cancer therapies, as its promiscuous clientele of proteins allows a single drug multi-target approach [137]. Additionally, HSP90 inhibitors have been found to effect both the non-stem cancer cell population and the cancer stem cell population [138], which is often resistant to common anti-cancer therapies [124,139–141]. However, there are now reports of Hsp90-client protein complexes from clinical samples that appear resistant to GA treatment [142]. HSP90 inhibition also often induces the expression of other HSP [143] through the activation of Heat Shock Factor 1 (HSF1) [144]. HSF-1 induces the expression of numerous HSP, and as such tumour cells are capable of compensating for HSP90 inhibition [13,144]. A crucial element to this compensatory mechanism is believed to be the HSF1-stimulated up-regulation of HSP70, that has been identified as a drug target in cancer due to its over-expression in cancer cells [76,145] and its role in cancer cell survival and proliferation [146,147]. Targeting HSP70 presents a challenge as selective targeting of certain HSP70 isoforms results in the up-regulation of alternative isoforms

capable of compensating for the inhibition [148–150], thereby promoting resistance to the HSP70 inhibitor. As such anti-cancer therapies targeting HSP70 will need to overcome this compensation by targeting multiple HSP70 isoforms, while the combination of HSP90 and HSP70 inhibition could enhance the efficacy of treatment more than the targeting of a single chaperone family [148]. These results lead to the proposal of using inhibitors of HSF-1 that will inhibit the expression of numerous HSP simultaneously. However, in all these cases, the inhibition is not specific, due to the fact that HSP90 and HSP70 interact with numerous different client proteins. Therefore, at present, it is not possible to target a specific HSP90 or HSP70-client interaction in a cancer cell. The DNAJ family of proteins plays a pivotal role in HSP70 client binding and regulation and modulation of the HSP90-client multi-chaperone complex, with evidence suggesting direct physical interactions between selected DNAJ and HSP90 [61–63]. Therefore, the targeting of selected DNAJ may be one mechanism to specifically inhibit selected chaperone pathways. Using co-chaperones such as DNAJ as drug targets may offer greater selectivity than targeting HSP90 and HSP70. DNAJ proteins are already regarded as bona fide drug targets in other infectious diseases, such as malaria [151], and as prognostic markers in inflammatory diseases [152]. DNAJ, like HSP70 and HSP90, are over-expressed or deregulated in cancers [153]; and while there is currently little clarity as to which isoforms are over-expressed, there is evidence that specific DNAJ may correlate with specific types of malignancies (Table 1) [109,154,155]. Many more DNAJ are uncharacterised and have unknown functions and interactions. Therefore, of major importance is the analysis of the functions and client specificities of the DNAJ overexpressed in cancer or cancer stem cells in order to establish a causal link between selected DNAJ and cancer development. These studies may identify tumour-specific DNAJ drug targets or allow for the targeting of tumour-specific client maturation processes with specificity provided by the type of DNAJ expressed. Selected DNAJ have been found to be differentially expressed in cancer stem cell

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and stem cell populations (Table 2) , therefore there is the theoretical potential of targeting these isoforms to remove this therapeutically resistant population that is believed to be the driving force behind cancer recurrence [139]. Most of the DNAJ that are deregulated in cancer or cancer stem cells do not appear to be the canonical type I DNAJ. In the case of cancer cells, the canonical type I DNAJ, DNAJA1 (HDJ2) is tumour promoting, while the type II DNAJ function largely as tumour suppressor proteins apart from DNAJC9 (Table 1). Members of the diverse and largely uncharacterised type III group seem to predominate in terms of cancer and stem cell expression profiles and this may provide a unique therapeutic opportunity. If it were possible to target only a specific DNAJ type III isoform that was only expressed under pathological conditions, it would be possible to circumvent any potential side effects that would result from disruption of the constitutive HSP70–DNAJ chaperone complex in normal cells. Designing drugs that target only specific isoforms of DNAJ would be the challenge, despite the fact that modulation of a specific DNAJ–HSP70 interaction by a small molecule has been described [156,157]. In the case of targeting a single DNAJ, the drug would most likely not be directed against the conserved J domain but would focus on the other, less well conserved domains. By contrast, this structural diversity of DNAJ could provide complications for the targeting of multiple DNAJ with a single inhibitor, a complication that is not as evident for HSP90 and to a lesser degree for HSP70s that share a high structural similarity. With this being said, all DNAJ contain a J-domain that is essential for stimulation of and interaction with HSP70, providing the obvious site for targeting several, if not all, DNAJ. Given that the majority of DNAJ identified in cancer to date appear to be tumour suppressors, the therapeutic approach may rather be to induce the expression of these proteins, rather than inhibiting them. This could be achieved either through regulating the transcription of the endogenous genes [158] or by delivering them exogenously using gene therapy. However, what is currently lacking in the field is fundamental research into the function of many DNAJ isoforms and the description of functional redundancy between different isoforms. At present, there are at least 14 different DNAJ isoforms, predominantly from the type III DNAJ family, for which a function has yet to be described [25]. Therefore, the analysis of the function of these proteins and the identification of a causal link between specific DNAJ isoforms and malignancy must be prioritised for DNAJ to be viable drug targets. Conflict of interest None declared. Acknowledgements JNS is a postgraduate student funded by the National Research Foundation [NRF] Innovation Scholarship. The views reflected in this document are those of the authors and should in no way be ascribed to the NRF or Rhodes University. We have attempted to review the literature completely; however, we accept that we are not able to

cite all contributions to the field and apologise if we have inadvertently omitted any key contributions to this field.

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