POZ for effect – POZ-ZF transcription factors in cancer and development

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POZ for effect – POZ-ZF transcription factors in cancer and development Kevin F. Kelly and Juliet M. Daniel Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada

The BTB/POZ-ZF [Broad complex, Tramtrack, Bric a` brac (BTB) or poxvirus and zinc finger (POZ)-zinc finger] protein family comprises a diverse group of transcription factors. POZ-ZF proteins have been implicated in many biological processes, including B cell fate determination, DNA damage responses, cell cycle progression and a multitude of developmental events, including gastrulation, limb formation and hematopoietic stem cell fate determination. Consequently, dysfunction of vertebrate POZ-ZF proteins, such as promyelocytic leukemia zinc finger (PLZF), B cell lymphoma 6 (Bcl-6), hypermethylated in cancer 1 (HIC-1), Kaiso, ZBTB7 and Fanconi anemia zinc finger (FAZF), has been linked directly or indirectly to tumorigenesis and developmental disorders. Here, we discuss recent advances in the POZ-ZF field and the implications for the design of future studies to elucidate the biological roles of these unique transcription factors. Introduction The BTB (Broad complex, Tramtrack, Bric a` brac) transcription factors were so named because of a distinct and unique N-terminal BTB domain that was first identified in, and named after, the Drosophila proteins Broad complex, Tramtrack and Bric a` brac [1]. These factors are also known as, and are hereafter described as, poxvirus and zinc finger (POZ) proteins (see Glossary). The POZ domain has since been found in over 200 proteins [2,3] that are classified according to the presence of an N-terminal POZ domain and other functional C-terminal domains, such as kelch repeats (POZ-kelch), or DNA-binding zinc fingers (POZ-ZF) – the focus of this review (Figure 1). The founding invertebrate POZ-ZF members were all transcriptional repressors, and each regulated different Drosophila developmental processes. The broad-complex (BR-C) POZ-ZF transcription factors are essential for Drosophila metamorphosis, and BR-C mutants exhibit severe central nervous system disorganization following hormonal stimulation [4,5]. Tramtrack (Ttk) is a key regulator of compound eye development, and ablation of one or both isoforms of the ttk gene affects ommatidial cell development and causes irregular eye formation [6]. Finally, Bric a` brac (Bab) has been found to regulate Drosophila ovary morphogenesis and limb formation because bab mutants have impaired ovariolar terminal filament formation [7] and homeotic transformation of Corresponding author: Daniel, J.M. ([email protected]). Available online 22 September 2006. www.sciencedirect.com

Glossary Affinity maturation: the increase in the affinity of antibodies for antigen produced during a humoral (antibody-mediated) immune response. B cell clonal expansion: a key event in adaptive immunity, the proliferation of antigen-specific B cells in response to antigenic stimulation precedes their differentiation into effector cells. C2H2 Kru¨ppel-type zinc finger: a type of DNA-binding domain, approximately 25–30 amino acids long, characterized by two conserved cysteine and histidine residue pairs that coordinate a single zinc atom, which serves as a crucial determinant of zinc finger conformation. The primary sequence of this subset of zinc fingers resembles that of the Drosophila segmentation protein Kru¨ppel. Canonical Wnt signalling: the canonical Wnt signaling pathway regulates various cellular processes but is best known for its effects on development and cancer. The pathway initiates upon docking of extracellular Wnt ligands at the cell surface Frizzled receptors, and ultimately controls the Armadillo protein b-catenin, which translocates to the nucleus to function as a coactivator for transcription factors of the lymphoid enhancer factor/T cell factor (Lef/TCF) family. Isotype switching: a conversion of one antibody type to another, resulting from the genetic rearrangement of genes in B cells. Kelch domain: a repeat domain of 44–56 amino acids, usually occurring as 5–7 tandem copies that adopt a b-propeller structure, sometimes interacting with actin filaments. Polycomb group proteins: a group of proteins that repress the expression of homeotic genes, which regulate vertebrate and invertebrate development by controlling the characteristics of body segments. POZ (or BTB) domain: a highly conserved domain of approximately 100 amino acids present in >200 human proteins, which usually mediates protein–protein interactions. The POZ domain is frequently located at the N-terminus, whereas other functional domains (e.g. Kelch repeats or zinc fingers) are located at the C-terminus. POZ proteins with zinc fingers (POZ-ZF) often exist in multiprotein transcription repression complexes and, occasionally, transcription activation complexes. T cell-dependent antigen presentation: the display of antigens as peptide fragments on dendritic cells for the purpose of presentation to T cells. Xenopus double-axis phenotype: increased Wnt signaling in the developing Xenopus embryo can cause the formation of a secondary axis (head), indicative of the effect(s) of Wnt signaling on body axis specification.

the bristle pattern of tarsal segments [8]. These early Drosophila findings highlighted key developmental roles for POZ-ZF proteins, and were later supported through studies of vertebrate POZ-ZF proteins. The human genome encodes approximately 60 POZ-ZF proteins [2], including the cancer-associated proteins promyelocytic leukemia zinc finger (PLZF), B cell lymphoma 6 (Bcl-6), ZBTB7 [also known as leukemia/lymphoma related factor (LRF), osteoclast derived zinc finger protein (OCZF), factor binding to IST-1 (FBI-I) and previously called Pokemon], hypermethylated in cancer 1 (HIC-1), Fanconi anemia zinc finger [FAZF, also known as PLZF-like zinc finger protein (PLZP), testis zinc finger protein (TZFP) or repressor of GATA (ROG)] and Kaiso. The POZ domain is a 100 amino acid, highly conserved motif that mediates protein–protein interactions, often in the context of multiprotein transcriptional

0962-8924/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2006.09.003

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Figure 1. POZ domain structure and sequence alignment of selected POZ-ZF transcription factors. POZ-ZF proteins typically have an N-terminal POZ domain and varying numbers of C-terminal zinc fingers. POZ domain sequence alignment of various Homo sapiens POZ-ZF transcription factors using CLUSTALW reveals that POZ-ZF transcription factors share several highly conserved hydrophobic residues. Residues conserved in >75% of the POZ-ZF proteins aligned at the top are denoted by red arrowheads. Residues previously demonstrated to regulate POZ domain integrity, and thus either POZ homodimerization or corepressor recruitment [67], are highlighted by yellow arrowheads. A 13 amino acid (a.a.) insertion in HIC-1 might have a role in regulating its corepressor recruitment ability [68], and is denoted by an orange box. An unusual serine-rich tract, detected only in ZBTB4 [56], is denoted by a green arrowhead (the full sequence, not shown at the top owing to space limitations, is LPLPPATGGAAPNPATTTAASSSSSSSSSSSSSSSSASSSSSSSSSSPPPASPPA). Accession numbers for the proteins analyzed above are: Bcl-6 (P41182), PLZF (Q05516), HIC1 (Q14526), Kaiso (Q86T24), Msx-interacting-zinc finger 1 (MIZ1; Q13105), FAZF (NP_055198), ZBTB7 (NP_056982), ZBTB4 (Q9P1Z0), ZBTB38 (Q8NAP3), Bcl-6-associated zinc finger protein (BAZF; Q8N143), myoneurin (NP_061127), Affected by papillomavirus DNA integration in ME180 cells-1 (APM-1; NP_004788).

activation or repression complexes (Figure 1 and Box 1). The most highly conserved residues (i.e. >50% conservation) of the human POZ domain occur at 27 positions throughout the 100 amino acid region, and 15 of these residues are completely conserved in >60% of POZ-ZF proteins. POZ-ZF transcription factors generally interact with DNA via their zinc finger motifs (the majority of which are of the Kru¨ppel-like C2H2 type) to bring about chromatin modification and/or restructuring, and localized transcriptional activation or repression. Recently, crucial roles in diverse cellular processes were revealed for several vertebrate POZ-ZF proteins. These included roles in DNA damage responses and cell cycle progression in the context of tumorigenesis, and roles in gastrulation and limb formation during vertebrate development. Here, we present and integrate recent findings on the cellular roles and mechanisms of action of specific vertebrate POZ-ZF proteins, as they relate to cancer and development. www.sciencedirect.com

Roles for POZ-ZF transcription factors in cancer and/or development Since the initial discovery of POZ-ZF proteins in Drosophila, various vertebrate POZ-ZF proteins have been isolated and characterized, and many are linked directly or indirectly to developmental or tumorigenic processes (Table 1). The developmental roles of POZ-ZF proteins are supported primarily through knockout approaches in mice and other model systems. By contrast, POZ-ZF protein roles in tumorigenesis were, in many cases, established through the identification of specific chromosomal aberrations and/or epigenetic modifications involving POZ-ZF genes. PLZF and acute promyelocytic leukemia The human PLZF gene is located on chromosome 11 and occasionally undergoes a chromosomal translocation event, t(11;17)(q23;q21). This results in direct fusion of PLZF to the retinoic acid receptor a (RAR-a), in the

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Box 1. POZ-ZF transcriptional repression: recruitment of HDAC corepressor complexes or not? POZ-ZF proteins can elicit transcriptional repression through HDACdependent (Bcl-6, PLZF, Kaiso) or HDAC-independent (HIC-1) mechanisms. HDACs fall into three classes (class I, HDACs 1–3 and HDAC8; class II, HDACs 4–7 and 9–10; and class III, sirtuins) based on sequence homology to yeast HDACs. HDACs are recruited by sequence-specific transcriptional repressors to specific chromatin regions to catalyze the N-terminal deacetylation of histones and promote a ‘closed’ chromatin conformation that precludes transcription. HDACs exist in multiprotein complexes with distinct functions and specificities. For example, HDAC1 and HDAC2, coexist in at least three unique multiprotein complexes (containing either Sin3, NuRD–Mi2, or coREST) [74]. PLZF interacts directly with HDAC1, mSin3a, SMRT and NCoR via highly conserved residues in its POZ domain (Figure 1), and PLZFmediated transcriptional repression is sensitive to HDAC inhibitors [67,75]. Interestingly, PLZF also complexes with the class II HDAC4, and HDAC4–RNAi partially abrogates PLZF-mediated repression [76]. Similarly to PLZF, Bcl-6 also interacts with HDAC1 or HDAC2 and mSin3a, but it binds SMRT or NCoR in a mutually exclusive manner [77,78]. However, Bcl-6 also interacts with the class II HDACs, -4, -5 and -7, and it can recruit a unique Bcl-6-specific corepressor, BCoR [79,80]. Another Bcl-6 corepressor is the acute myeloid leukemialinked eight-twenty-one (ETO) protein [81]. Kaiso is a unique POZ-ZF transcription factor with bimodal DNAbinding properties. Kaiso binds the sequence-specific element (TCCTGCnA) and methylated CpG dinucleotides in target gene promoters [82–84]. Interestingly, Kaiso-mediated transcriptional repression is relieved by p120ctn [51,59,85]. Although the mechanism of

hematological malignancy acute promyelocytic leukemia (APL) [9]. Normally, unliganded RARs recruit corepressors that inhibit retinoid signaling. Upon RA binding to the receptor, RAR-a releases these corepressors and activates transcription of retinoid-responsive genes [10]. In APL, the mutant PLZF–RAR-a fusion protein also recruits the transcriptional corepressors Nuclear corepressor (NCoR), histone deacetylase 1 (HDAC1), silencing mediator of retinoid and thyroid hormone receptors (SMRT) and mammalian Swi-independent 3A (mSin3A) [11,12]. However, in this case, the presence of RA does not fully dissociate PLZF– RAR-a–corepressor interactions, and the mutant fusion protein behaves as a potent dominant negative inhibitor of wild-type RAR-a. This ultimately affects the expression of RAR-a targets such as genes involved in DNA repair, apoptosis and cell cycle [13–15]. The ability of

transcription repression of Kaiso via the sequence-specific sites is unclear, evidence implicates recruitment of the HDAC1–mSin3a corepressor complex (J.M. Daniel and R. Eisenman, unpublished). By contrast, transcriptional repression from methylation-dependent sites (e.g. the MTA2 locus) requires recruitment of HDAC3–NCoR corepressors [84]. Kaiso also binds the chromatin insulator protein CTCF [72] and is postulated to regulate CTCF-mediated gene expression. Whether CTCF reciprocally modulates Kaiso transcriptional activity is currently unknown. Unlike Bcl-6, PLZF and Kaiso, HIC-1 [86] and its avian homolog gF1binding protein isoform B (gFBP-B) [68] can repress transcription independently of HDACs. Furthermore, HIC-1 has a unique 13 a.a. insertion in its POZ domain, and it was postulated that this insertion might prevent HIC-1 interaction with HDAC-1, NCoR, SMRT or Sin3a [68]. However, HIC-1 can recruit the corepressor C-terminal-binding protein (CtBP) and coprecipitate HDAC activity through an evolutionarily conserved motif (GLDLSK[K/R]) outside of the POZ domain [87]. In addition, HIC-1 binds the class III HDAC SIRT1 and modulates its activity during p53-dependent DNA damage responses [46]. Interestingly, the HIC-1–SIRT1 interaction appears to require the HIC-1 POZ domain, and whether the 13 a.a. insert is requisite for the interaction is unknown. The preferential recruitment of specific corepressors by POZ-ZF transcription factors might be dictated by upstream signaling pathways (Figure 2) and/or their structural conformation at target gene promoters. Nevertheless, the variety of putative target genes regulated by POZ-ZF transcription factors (Figure 2) reflects the diversity of cellular processes they regulate.

PLZF–RAR-a to trigger transformation was shown to be dependent on the homodimerization or multimerization of the PLZF–RAR-a fusion proteins, which, in contrast to monomers, recruit corepressors robustly [16]. Thus, blocking the homodimerization of RAR-a fusion proteins, such as with peptide inhibitors, might represent a novel means of therapy for patients with APL. Recently, wild-type PLZF was directly linked to tumor suppression via its transcriptional repression of the c-myc oncogene; this triggered cell growth inhibition and cell quiescence [17]. If the PLZF–RAR-a fusion proteins lack this repression ability, it might explain the increased proliferation of myeloid cells observed in APL. Alternatively, the finding that PLZF–RAR-a inhibits p53 tumor suppressor activity (Figure 2) by promoting p53 degradation might explain the increased proliferation of APL cells

Table 1. Putative cellular roles of vertebrate POZ-ZF transcription factors Protein name PLZF Bcl-6

Repressor, activator or both? Repressor Repressor

FAZF MIZ–1 HIC–1

Repressor Both Repressor

ZBTB7 Kaiso BAZF APM-1

Repressor Both Repressor Repressor

Nac-1 ZBTB38 ZBTB4

Repressor Repressor Repressor

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Putative function(s)

Refs

Limb development; gene regulation in APL Plasma cell fate; germinal center formation; germ cell apoptosis; gene regulation in B cell lymphoma T cell proliferation; cytokine production; hematopoietic stem cell proliferation Gastrulation; cell cycle progression; regulator of Myc-mediated gene regulation Tumor suppressor; craniofacial development; DNA damage responses; inhibition of Wnt signaling Proto-oncogene; regulator of oncogenesis; stimulator of HIV1 Tat activity Gastrulation; canonical and noncanonical Wnt signaling; regulator of synapse formation Activation of naı¨ve T cells Possible tumor suppressor; cell growth inhibition; downregulated in cervical carcinoma cell lines Neuronal apoptosis; behavioral sensitization to cocaine; regulation of p53 levels? (Figure 2) Expression in late postmitotic neurons; function unknown Ubiquitous expression; function unknown

[19,20] [25,31,32,40] [65] [88,89] [44,46,73] [61,90] [51,52,59,91] [92] [93] [70,71] [56,94] [56]

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differentiation of mitotic germ cells in the testis (spermatogonia) into mature spermatozoa. PLZF / mice exhibit smaller testes, and a progressive loss of spermatogonia into adulthood relative to heterozygote or control littermates [22]. However, in contrast to the proapoptotic role of PLZF in the limb bud [19], PLZF appears to be antiapoptotic in the developing testis because PLZF / mice display increased apoptosis of cells in seminiferous tubules, the sites of spermatozoa maturation. The roles of PLZF thus appear to be context dependent, and probably temporally and spatially regulated throughout development. Figure 2. Involvement of POZ-ZF proteins in the p53 pathway. The POZ-ZF proteins HIC-1, Bcl-6, PLZF and Nac-1 have been linked directly or indirectly to p53 regulation. When HIC-1 is expressed, it acts with p53 to inhibit tumorigenesis in mouse models [45]. This occurs, in part, through HIC-1- and SIRT1-mediated transcriptional repression of the SIRT1 gene [46]. However, upon epigenetic downregulation of HIC-1, a frequent event in human cancers, SIRT1 is expressed and subsequently deacetylates and inactivates p53, thereby preventing apoptosis. Expression of p53 might also be controlled by Bcl-6, which directly regulates p53 expression in germinal center B cells [27]. Although Bcl-6 might be expressed in cells outside of the lymphatic system [69], whether Bcl-6 regulates p53 expression and regulates tumor formation in other cell types is currently unknown. Nac-1 expression in terminally differentiated neurons of the adult brain increases after cocaine exposure [70]. Interestingly, adenovirus-mediated overexpression of Nac-1 in immortalized neurons induced cell death, and was accompanied by increased p53 expression [71], although whether Nac-1 directly augments p53 transcription is unclear. Finally, expression of APL-associated PLZF-RAR-a might inhibit the stability of p53, enabling APL cells to evade cell death and proliferate [18].

[18]. Together, these findings indicate that PLZF and PLZF derivatives can affect tumorigenesis through multiple mechanisms, transcriptional and nontranscriptional, and highlights the functional complexity of POZ-ZF transcription factors. PLZF: a regulator of limb and skeleton formation Although the mutant PLZF–RAR-a fusion proteins were acknowledged for their role in cancer, the role of wild-type PLZF was elucidated only recently, using mouse models. Homozygous disruption of the PLZF (Zfp145) gene in mice caused notable limb and axial skeletal abnormalities [19], including homeotic transformation of hindlimb anterior skeletal structures into posterior structures. This was attributed to decreased apoptosis and increased proliferation of developing limb structures, and indicates a proapoptotic role for PLZF. Furthermore, PLZF-null mice misexpressed genes encoding bone morphogenic proteins (BMPs) and Hox family proteins (including Hoxd9, Hoxd10 and Hoxd11), which normally regulate limb morphogenesis [19]. PLZF possibly regulates Hox gene expression through chromatin remodeling; PLZF recruited the polycomb protein Bmi-1 to Hoxd11 regulatory sites, and prevented access of transcriptional activators [20]. Recently, cooperation between PLZF and GLI–Kru¨ppel family member 3 (Gli3) in limb formation was also reported [21]. These studies reveal a central role for wild-type PLZF in vertebrate limb patterning by regulating the expression of BMPs and Hox family genes that modulate apoptosis and cell proliferation in limb structures. In addition to the above-mentioned roles in limb formation, PLZF also regulates spermatogenesis, the www.sciencedirect.com

Bcl-6 and B cell lymphoma Bcl-6 was originally identified as a gene frequently involved in chromosome 3 and 14 translocation events in nonHodgkin’s lymphomas (NHL) [23], and its wild-type protein product functions as a sequence-specific transcriptional repressor [24]. NHL comprises a diverse group of diseases, the most common of which is diffuse large B cell lymphoma (DLBCL). It has been found that 35% of DLBCL occurrences involve Bcl-6 translocation events with various genes on different chromosomes [23]. Because the translocation breakpoints most often involve the 50 regulatory region of Bcl-6, the Bcl-6 gene is misexpressed owing to the inappropriate integration of heterologous promoters (most often those of immunoglobulins) proximal to its coding region [23]. Importantly, Bcl-6 expression and/or function can also be affected by somatic hypermutations within the 50 noncoding regulatory region of the Bcl-6 gene [23]. Despite the overwhelming circumstantial evidence linking Bcl-6 to BCLs, in vivo evidence of Bcl-6 oncogenicity was, until recently, lacking. Using transgenic mouse models, two independent studies recapitulated features of DLBCL in mice by expressing a mutant form of Bcl-6 in lymphocytes that mimicked the t(3;14)(q27;q32) translocation event observed in some DLBCL patients [25,26]. One study found that mutant Bcl-6 transgenic mice exhibited increased germinal center formation and dysregulated postgerminal center differentiation capacity, leading to an overall reduction in total serum immunoglobulin levels [25]. Subsequent analysis of transgenic mice aged 15–20 months revealed that, depending on the strain, 30–60% of mice developed BCLs [25]. By contrast, another study [26] found that only 13% of Bcl-6 transgenic mice harboring the same translocation developed spontaneous lymphomas. However, lymphoma incidence was augmented significantly relative to control littermates after treatment with the carcinogen N-ethyl-N-nitrosourea (ENU), an alkylating agent that induces DNA point mutations [26]. The different outcomes of these two studies might be due to the use of different mouse strains between the two (C57BL/6 [25] versus FVB/N [26]), and possibly also the tetracycline-responsive system used by the latter study [26]. Although little is known regarding which Bcl-6 target genes promote lymphoma incidence, a recent report revealing p53 as a direct target of Bcl-6 (Figure 2) suggests that inhibition of this key tumor suppressor might be a contributory factor [27]. Overall, these studies confirmed the causative role of Bcl-6 translocation events in the pathogenesis of BCL.

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At least two options exist for the treatment of patients with BCL due to Bcl-6 translocation events: (i) prevent the initial inappropriate expression of Bcl-6, or (ii) inactivate or deplete the overexpressed form of Bcl-6 protein. Recently, two independent studies [28,29] adopted the latter approach and demonstrated that cell-penetrating peptides, specifically targeting the Bcl-6 POZ domain, inhibit Bcl-6mediated transcriptional repression. In one study [28], these peptides, designed using recent Bcl-6-POZ crystal structure data [30], potently perturbed Bcl-6–corepressor interactions, blocked germinal center formation and recapitulated the phenotypes of Bcl-6/ mice. Because peptide treatment also triggered cell cycle arrest and apoptosis in BCL cell lines, such small molecule inhibitors might prove efficacious for the in vivo treatment of BCL. Bcl-6: a master regulator of germinal center formation and B cell fate Bcl-6-deficient mice are viable but demonstrate significantly impaired germinal center formation and inflammatory responses [31]. Because the germinal center is the site of B cell clonal expansion, affinity maturation and isotype switching after T cell-dependent antigen presentation, Bcl-6-deficient mice are highly immunologically compromised. Bcl-6 was linked to B cell differentiation because it represses active germinal center B cell differentiation into terminally differentiated B cells (i.e. antibody-producing plasma cells that mediate the humoral immune response by recognizing foreign antigens and targeting them for destruction [32]). Microarray studies suggested that many genes under Bcl-6-mediated transcriptional repression in germinal center B cells were involved in lymphocyte activation and differentiation, inflammatory responses or cell cycle progression [33]. One of the genes identified through microarray methodologies was PRDM1, which encodes B lymphocyte-induced maturation protein 1 (Blimp-1), a zinc-finger transcriptional repressor that drives the transition of undifferentiated B cells into antibody-secreting plasma cells [34]. Bcl-6 regulation of PRDM1 expression occurs via a complex mechanism, possibly involving the transcriptional activator signal transducer and activation of transcription (Stat) 3 [35], Bcl-6 acetylation status [36], mitogen-activated protein kinase (MAPK)-mediated Bcl-6 phosphorylation status [37], Stat5-mediated Bcl-6 expression levels [38] and the recruitment of a transcriptional repression complex containing NCoR and a cell-typespecific subunit, Metastasis-associated protein 3 (MTA3) [39]. Interestingly, similarly to PLZF-null mice, Bcl-6-null mice also exhibit decreased numbers of testicular spermatozoa, and increased apoptotic spermatocytes at metaphase I, suggesting an antiapoptotic role [40]. Increased levels of the proapoptotic protein Bax in the testes of Bcl-6/ mice 6 [40], and the identification of programmed cell death 1 gene (PDCD2) as a Bcl-6 target further support an antiapoptotic role for Bcl-6 [41]. Although early development is similar between Bcl-6+/+ and Bcl-6/ mice, Bcl-6/ mice exhibited a significantly decreased capacity to reproduce. This highlighted the importance of Bcl-6 in reproductive organ function [40]. www.sciencedirect.com

Collectively, these studies underscore the important and unique immunological and reproductive roles of Bcl-6. Cooperation between the tumor suppressors HIC-1 and p53 HIC-1 was first identified by virtue of its proximity to the p53 gene on human chromosome 17p13.1, and its hypermethylation and resulting underexpression in tumor cells [42,43]. These findings, coupled with the fact that HIC-1 expression could be induced by wild-type p53 [42], led to the hypothesis that HIC-1 was a novel tumor suppressor. Indeed, although homozygous deletion of HIC-1 in mice is embryonically and perinatally lethal [44], heterozygotes exhibit an array of gender-dependent malignant tumors: males predominantly develop carcinomas (75% of tumors formed) and females develop sarcomas or lymphomas (85% of tumors formed) [44]. Interestingly, in most tumor samples examined from HIC-1+/ mice, the functionality of the remaining wild-type allele was lost, owing to hypermethylation of the HIC-1 promoters [44]. Recently, it was demonstrated that simultaneous trans loss of HIC-1 and p53 on mouse chromosome 11, relative to p53 loss alone, yields a higher incidence of aggressive osteosarcomas [45]. Importantly, the observed phenotypes were accelerated and more aggressive when p53 and HIC-1 were inactivated on the same chromosome, due in part to the increased inactivation of remaining p53 and HIC-1 wild-type alleles through deletion [45]. These findings suggest a vital link between the epigenetic (HIC-1) and genetic ( p53) silencing of tumor suppressor genes in cancer. The specific mechanism through which HIC-1 regulates tumorigenesis involves the formation of a transcriptional repression complex with the class III Sirtuin 1 (SIRT1) deacetylase; the HIC-1–SIRT1 complex then binds and represses transcription from the SIRT1 promoter [46]. Under normal conditions, SIRT1 is prevented from deacetylating and inactivating p53. However, upon loss of HIC-1 expression, as in many cancers, SIRT1 expression levels increase and p53 is inactivated [46]. Consequently, HIC-1-lacking cells are resistant to DNA damage-induced, p53-mediated apoptosis. Intriguingly, as depicted in Figure 2, these studies also reveal a potential feedback loop, whereby: (i) HIC-1 represses transcription of SIRT1; (ii) SIRT1 deacetylates and inactivates p53; and (iii) p53 activates transcription of HIC-1 [46]. Therefore, upon epigenetic loss of HIC-1 (as a result of aging and/or environmental factors), SIRT1 might become upregulated, deacetylate p53, and inhibit p53 growth control and proapoptotic functions [46] (Figure 2). Constitutive inhibition of p53 by this or other mechanisms might further compromise its ability to induce HIC-1 expression, further promoting SIRT1 expression and p53 acetylation and inactivation. The net result might then be uncontrolled proliferation of tumorigenic cells. HIC-1: a crucial factor for embryonic development The tumor suppressor gene HIC-1 is located on chromosome 17 in a region deleted in Miller–Dieker syndrome patients. This neuronal migration disorder is characterized by smoothness of the brain surface (lissencephaly) and distinct facial abnormalities [47]. HIC-1/ mice die perinatally and

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exhibit a range of developmental defects, including overall developmental delay, stunted growth, craniofacial defects, and, in some cases, acrania (partial absence of skull) and exencephaly (exposure of the brain) [48]. Although little is known about the underlying molecular mechanisms of Miller–Dieker syndrome, loss of HIC-1 might be a key contributory factor to this developmental syndrome. Kaiso: a negative regulator of Wnt signaling in tumorigenesis? Unlike many vertebrate POZ-ZF proteins that were first isolated through their direct links to cancer (e.g. Bcl-6, PLZF, HIC-1), Kaiso was first discovered as a binding partner for the Src kinase substrate and cell adhesion catenin p120ctn [49], which is now known to also be a key regulator of Rho–GTPase activity and cadherinmediated cell adhesion [50]. As an unexpected nuclear binding partner for p120ctn, Kaiso was postulated to couple cell surface adhesion and nuclear gene regulatory events in tumorigenesis [2,49]. This hypothesis was supported by recent evidence that Kaiso inhibits b-catenin-mediated transactivation of the Wnt signaling target genes encoding matrix metalloproteinase 7 – also known as matrilysin – (MMP7) in human cells [51] and siamois in Xenopus laevis [52] (Figure 3). MMP-7 encodes a matrix metalloproteinase directly linked to tumor metastasis through its upregulation in some cancers and proteolysis of the extracellular matrix and substrates such as E-cadherin and b4 integrin [53]. The notion that Kaiso is a negative regulator of canonical Wnt signaling (which is highly conserved throughout evolution and has a key role in embryonic growth and development) was strengthened by studies in the Xenopus model system [52]. In Xenopus, aberrant activation of canonical Wnt signaling results in embryos with an unusual double-axis phenotype (two heads), owing to the prominent role of Wnt signaling in body axis formation. Strikingly, Kaiso overexpression rescued the Wnt-induced Xenopus double-axis phenotype. In humans, inappropriate activation of the canonical Wnt signaling pathway is known to be directly associated with tumorigenesis because many Wnt target genes are associated with cell proliferation or invasion [54]. Therefore, these studies were the first to experimentally link Kaiso to the regulation of Wnt signaling and, possibly, tumorigenesis. Surprisingly, however, Kaiso-null mice did not develop tumors, and were viable and healthy [55]. However, when Kaiso-null mice were crossed with the well-characterized Apcmin/+ mice that develop intestinal polyps, polyp formation was delayed in the progeny [55]. This suggests that mammalian Kaiso cellular function differs significantly from that of Xenopus Kaiso. Alternatively, the highly related POZ-ZF proteins ZBTB4 [Kaiso-like 1 (Kaiso-L1)] and/or ZBTB38 [56] or other methyl-binding proteins might substitute for Kaiso function in Kaiso-null mice. Because ZBTB4 recognizes the sequence-specific Kaisobinding site and also methyl-CpGs [56], Kaiso and ZBTB4 might share target genes, and ZBTB4 might compensate for Kaiso loss and explain the normal phenotype of Kaisonull mice. These and other possibilities should be addressed through combinatorial knockouts between www.sciencedirect.com

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Kaiso and these related genes, both in mice and cultured cells, to elucidate Kaiso function in tumorigenesis. A study to examine the expression pattern of Kaiso in human tumor tissue surprisingly revealed that, in contrast to cultured cells, in human tissues Kaiso often localized to the cytosol rather than the nuclei [57]. Furthermore, when cultured cells with nuclear Kaiso were xenografted onto nude mice, the subcellular localization of Kaiso shifted to the cytoplasm, and in some cells Kaiso expression was lost altogether [57]. However, this effect was reversible; upon removal of xenografted cells and their return to culture, Kaiso was re-expressed and detected in the nuclear compartment. These data suggest an unexpected role for the tumor microenvironment on Kaiso subcellular localization. One pertinent question is whether, under specific circumstances, Kaiso nuclear import is impaired owing to mutational or post-translational inactivation of its nuclear localization signal [58], or Kaiso nuclear export is enhanced. Alternatively, Kaiso might be sequestered by a cytosolic binding partner, such as p120ctn. Nevertheless, these observations indicate that the subcellular localization of Kaiso is dynamic rather than static, and it is now vital to determine the upstream signaling pathway(s) regulating the subcellular localization and/or activation state of Kaiso. Additionally, definitive studies to correlate Kaiso expression and subcellular localization with tumor grade and/or prognosis will provide insights into the relevance of Kaiso in tumorigenesis. Kaiso is required for Xenopus development but not mouse development In striking contrast to Kaiso-null mice which had no overt developmental phenotypes [55], Kaiso-depleted Xenopus embryos exhibited gastrulation defects, specifically in convergent extension [59]. This effect was attributed to dysregulation of the Wnt-11 target gene involved in noncanonical Wnt signaling. In another Xenopus study, Kaiso depletion triggered embryonic apoptosis due to inappropriate global gene activation, as determined by microarray analyses [60]. One explanation for the significant effect(s) after Kaiso depletion in frogs, but not in mice, might be the functional redundancy between Kaiso and ZBTB4 and ZBTB38 [56]. Additional studies, such as cosuppression of Kaiso, and ZBTB4 or ZBTB38 in mouse models, are necessary to resolve this issue of redundancy. ZBTB7: a novel proto-oncogene and regulator of tumorigenesis ZBTB7 is a recently characterized POZ-ZF protein that was identified as a crucial regulator of the tumor suppressor p19Arf [61]. The p19Arf promoter contains multiple ZBTB7-binding sites, and was directly subject to ZBTB7mediated transcriptional repression [61]. Depletion of ZBTB7 inhibited the transformation potential of combinations of various established oncogenes (Myc, H-rasV12 and T-antigen) in mouse embryonic fibroblasts (MEFs) [61]. This implicated ZBTB7 as a unique, central ‘gatekeeper’ of tumorigenesis through these oncogenes. Furthermore, retrovirus-mediated ZBTB7 overexpression, along with the Myc, H-rasV12 or T-antigen oncogenes, triggered foci formation of MEFs in soft agar assays [61]. The

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Figure 3. Model of POZ-ZF transcription factor gene regulation and function. Although the DNA-binding properties of many POZ-ZF transcription factors have been elucidated, comparatively little is known about their bona fide target genes or the upstream signaling pathways that ultimately regulate POZ-ZF transcriptional activity. Bcl-6 is phosphorylated by MAPKs and targeted for proteasomal degradation in response to antigen receptor signaling (green receptor) [61]. The bimodal transcription factor Kaiso might be a downstream effector of receptor tyrosine kinase (RTK) (orange receptor) or adhesion signaling because it is negatively regulated by its binding partner p120ctn [2], which is a Src kinase substrate and member of the E-cadherin–catenin complex. Kaiso function might also be regulated by the chromatin insulator protein CCCTC-binding factor (CTCF) [72]. Interestingly, both Kaiso and HIC-1 have been linked to inhibition of Wnt signaling [51,52,73]. Target genes that might contribute to hematological or solid tumor malignancies are in red, and those contributing to vertebrate development are in blue. Additional modes of regulation of Bcl-6, Kaiso and other POZ-ZF proteins probably exist and are likely to be the focus of ongoing studies.

transforming potential of ZBTB7 was elegantly confirmed in vivo using transgenic mice overexpressing ZBTB7 in immature T and B lymphoid cells; these mice developed tumors and exhibited tumor infiltration of bone marrow. These observations, coupled with the high expression levels of ZBTB7 in lymphomas and other cancers [61], make ZBTB7 an attractive target for the design of anticancer therapeutics because targeted inhibition of ZBTB7 might attenuate tumorigenesis caused by established oncogenes in vivo. FAZF and the cancer susceptibility syndrome FA FAZF was originally identified as a binding partner for the FA group C protein (FANCC) [62], encoded by one of at least 11 genes mutated in patients with FA. FA is an autosomal or X-linked recessive disease characterized by hypersensitivity to DNA-crosslinking agents. Although FA is phenotypically heterogeneous, those affected usually exhibit a combination of progressive bone marrow failure, www.sciencedirect.com

congenital developmental defects, and susceptibility to hematological cancers, or less frequently, squamous cell carcinomas [63]. Interestingly, the region of FANCC mutated in FA patients is required for the FANCC–FAZF interaction, which suggests that loss of this interaction might promote FA. Although this hypothesis has yet to be proven in vivo, it is worth noting that forced expression of FAZF in a myeloid cell line promotes G1 cell cycle arrest, and triggers cellular apoptosis [64]. Whether FAZF is overexpressed in the hematopoietic stem cell (HSC) compartment of patients with FA is unknown but the apparent proapoptotic role for FAZF in myeloid cells might explain the FA bone marrow failure phenotype attributed to insufficient expansion and increased apoptosis of HSCs. Interestingly, mouse knockout studies also support a proapoptotic role for FAZF [65]. FAZF-null mice are viable and, in contrast to PLZF-null mice, generate sperm and are fertile [65]. However, FAZF-deficient mice exhibit increased T lymphocyte cell proliferation, and increased

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cytokine production from CD8+ and CD4+ T cells. Importantly, these animals have increased numbers of HSCs in the G1 phase of the cell cycle, supporting a novel role for FAZF in proliferation of this cellular niche [65]. However, the molecular mechanism underlying this role is currently unknown. Concluding remarks Since the initial characterization of Drosophila POZ-ZF proteins over 20 years ago, work from various laboratories has solidified important roles for vertebrate POZ-ZF transcription factors in development and tumorigenesis through their direct or indirect modulation of gene expression. For those POZ-ZF proteins whose molecular mechanism of action is not yet understood, a key research priority is to elucidate the upstream signaling pathways that modulate their activity (Figure 3). Elucidating (i) how POZ-ZF proteins are post-translationally modified (i.e. phosphorylated, acetylated or sumoylated), and (ii) how these modifications regulate POZ-ZF protein activity, will be central to understanding their functions and mechanisms of action. Also, because some POZ-ZF proteins heterodimerize via their POZ domains (e.g. Bcl-6 and PLZF [66], FAZF and PLZF [62]), it is likely that some POZ-ZF proteins reciprocally regulate the activity of the other. Knockdown and transgenic approaches will be integral for clarifying POZ-ZF protein in vivo roles and resolving redundancy issues (such as between Kaiso and ZBTB4). Interestingly, some POZ-ZF proteins are linked mainly to hematological cancers (e.g. PLZF, Bcl-6 and FAZF), and others are linked to solid tumors (e.g. HIC-1, ZBTB7 and Kaiso). Determining whether this difference is due to tissue-specific expression of POZ-ZF proteins, or to other intrinsic POZ-ZF protein properties, will clarify their overall functional mechanisms. Finally, additional crystal structure studies might provide further insight into the assembly of macromolecular POZ-ZF transcriptional complexes and their mechanics of transcriptional activity. Acknowledgements We are indebted to members of the Daniel laboratory for helpful comments and insights regarding this manuscript, particularly Kyster Nanan for help with the POZ-ZF protein sequence analysis. We also acknowledge those laboratories whose fine work could not be cited owing to space constraints. K.F.K. was supported by NSERC D2 and CIHR Doctoral Research Awards and the Lee Nielson Roth Cancer Research Award. J.M.D. was funded by CIHR research grant MOP-66963 and DOD Breast Cancer IDEA grant DAMD17–02–1-0479. This article is dedicated to the memories of the late R.A.H. and E.S.

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