FKBPs in chromatin modification and cancer

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FKBPs in chromatin modification and cancer Ya-Li Yao1,3, Ya-Chen Liang2,3, Huai-Huei Huang2 and Wen-Ming Yang2 FK506-binding proteins (FKBPs) are intracellular receptors for FK506 and rapamycin, immunosuppressants that have recently been utilized as anticancer drugs. In the cytoplasm, FKBPs and these drugs modulate signal transduction pathways. However, recent reports reveal novel functions of FKBPs in the nucleus, which include regulation of transcription factors, histone chaperone activity, and modifications of chromatin structure. These activities are known to affect gene expression, DNA repair, and DNA replication. Therefore, elucidation of the nuclear functions of FKBPs will help researchers and clinicians better understand how immunosuppressants work as anticancer drugs, which might in turn lead to novel designs of cancer therapy. Addresses 1 Department of Biotechnology, Asia University, Taichung 41354, Taiwan 2 Institute of Molecular Biology, National Chung Hsing University, Taichung 40227, Taiwan Corresponding author: Yang, Wen-Ming ([email protected]) These authors contributed equally to this work.

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Current Opinion in Pharmacology 2011, 11:301–307 This review comes from a themed issue on Cancer Edited by Maria Fiammetta Romano Available online 12th April 2011 1471-4892/$ – see front matter # 2011 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2011.03.005

Introduction FK506-binding proteins (FKBPs) were identified based on their ability to bind immunosuppressant drugs. They function in signal transduction pathways that relay signals into the nucleus to activate transcription during immunoresponses. Most of the FKBP family members identified to date reside in the cytoplasm. FKBP12 and FKBP13 bind mammalian target of rapamycin (mTOR) complexes (reviewed in Ref. [1]). FKBP51 and FKBP52 function as cochaperones for Hsp90 and regulate the translocation of steroid hormone receptors from the cytoplasm into the nucleus (reviewed in Ref. [2]). The function of FKBPs in the nucleus was discovered relatively late. The first mammalian FKBP that was found to be located in the nucleus is FKBP25, which functions in transcriptional regulation and chromatin modification [3]. Two more nuclear FKBPs (Fpr3 and Fpr4) that are related to FKBP25 were identified in yeast [4,5], and the characterization of their functions shed new light on the role of FKBPs in the nucleus. www.sciencedirect.com

Because abnormally high activity of mTOR, especially in cells lacking functional PTEN, causes derailed protein synthesis and tumor growth, there has been intense interest in the link between FKBPs and cancer. The success of using immunosuppressants FK506 and rapamycin to treat cancer further highlights the potential of targeting FKBPs in cancer therapy. It was recently found that the expression level of FKBP51 is increased in prostate cancer [6]. Specific knockdown of the expression of FKBP proteins is able to promote apoptosis in cancer cells [7]. These results suggest that FKBPs are important players in the formation of cancer. Relative to the function of FKBPs in the cytoplasm, the role of FKBPs in the nucleus is less clear. Nuclear events and processes such as gene transcription, DNA repair, and DNA replication have crucial ramifications to the formation and progression of cancer. Fortunately, recent publications offer a glimpse into the role of FKBPs in the nucleus, which is important to a more comprehensive understanding of the relationship between FKBPs and cancer. Here we highlight recent discoveries on the functions of FKBPs in the nucleus, focusing on how FKBPs regulate transcription, how they function as histone chaperones, and how they modify chromatin structure.

FKBPs regulate transcription factor activities The first report on the involvement of FKBPs in transcription is from the discovery of the interaction between FKBP12 and YY1 through a yeast two hybrid screen using YY1 as bait [8]. FKBP12 was found to relieve the repressional activity of YY1, and the interaction between FKBP12 and YY1 was disrupted by FK506. In a subsequent report, FKBP12, fused to a Gal4-DNA binding domain which forced the fusion protein to a target promoter in mammalian cells, activated transcription when rapamycin was added [9]. These results suggest that FKBP12 activates transcription when recruited to a target promoter through interaction with YY1. Furthermore, FK506 or rapamycin might disrupt the interaction between FKBP12 and YY1, releasing FKBP12 from YY1 and causing YY1 to become a repressor. This possibility was confirmed by a recent finding that an FKBP12 target protein, TORC1, is recruited by YY1 to YY1 target promoters, forming an activation complex containing coactivator PGC-1a [10]. Moreover, addition of rapamycin disrupts the activation complex and turns YY1 into a repressor. We speculate that these two reports are probing the same model and FKBP12 is part of the YY1/TORC1/ PGC-1a activation complex. Binding of FK506 or Current Opinion in Pharmacology 2011, 11:301–307

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Figure 1

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Regulation of transcription factor YY1 by FKBP12. (a) FKBP12 is recruited to the promoter by YY1, which activates transcription. Addition of FK506 blocks the interaction between YY1 and FKBP12, releases FKBP12, and causes repression of YY1 target genes. (b) FKBP12 is part of the activator complex containing YY1, TORC1, and PGC-1a. Rapamycin disrupts the complex, turning YY1 into a transcriptional repressor.

rapamycin to FKBP12, which disrupts the protein complex and releases FKBP12 from the promoter, might be the underlying mechanism of switching YY1 from an activator to a repressor upon administration of an immunosuppressant (Figure 1). Later, YY1 was demonstrated to interact with another FKBP member, FKBP25 [3]. Whereas YY1 interacts with FKBP12 at the conserved PPIase domain, which constitutes almost the full length of FKBP12, YY1 only interacts with the N-terminal charged region unique to FKBP25. Interestingly, rapamycin or FK506 has no effect on the interaction between YY1 and FKBP25. Although EMSA experiments showed that the interaction increases the DNA-binding activity of YY1, which may enhance YY1’s repressional activity, this increase in YY1’s DNA-binding activity by FKBP25 is not affected by FK506 or rapamycin, consistent with the result from protein interaction assays. Moreover, FKBP25 also interacts with HDAC1 and HDAC2. These results suggest that FKBP25 functions as a scaffold protein to assemble histone deacetylase activity around YY1 (also see discussion in the FKBPs and chromatin section). These findings further demonstrate the functional diversity of FKBPs in the regulation of a single transcription factor, YY1. Unlike FKBP25, whose PPIase activity appears to play no regulatory role in the DNA-binding activity of YY1, FKBP52 is the first FKBP in which the PPIase activity changes the DNA-binding activity of a transcription Current Opinion in Pharmacology 2011, 11:301–307

factor called IRF-4 [11]. FKBP52 was identified as an IRF-4 binding partner from a yeast two hybrid screen. Although the interaction between FKBP52 and IRF-4 does not involve their PPIase domain and DNA-binding domain, EMSA experiments demonstrated that FKBP52 inhibits the DNA-binding activity of IRF-4, whereas the inhibition can be reversed by a PPIase inhibitor. These results suggest that FKBP52 is a coregulator for IRF-4’s transcriptional activity, possibly through modification of protein factors that interact with IRF-4. Given its ubiquitous expression, FKBP52 might be an inducible, transcriptional coregulator. How FKBP52 can be induced or activated to regulate IRF-4 remains to be elucidated. FKBP51 and FKBP52 have been known for their cochaperone activity in steroid hormone responses. Their PPIase activity appears to be important for their role as cochaperones of Hsp90 during the process of translocation of steroid hormone receptors from the cytoplasm into the nucleus upon ligand binding [12]. Recent results showed that such cochaperone complexes exist not only in the cytoplasm but also in the nucleus [13,14]. Experiments using Fkbp52-null cells suggest that FKBP52 is required for the transactivation activity of androgen receptors located in the nucleus [15]. These results show that FKBP51 and FKBP52 might regulate transcription at the site of gene promoters; however, more evidence (such as chromatin immunoprecipitation assay results) is needed to confirm this hypothesis. www.sciencedirect.com

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In another yeast two hybrid screen using MDM2 as bait, FKBP25 was found to be a partner of p53-regulating factor MDM2 [16]. FKBP25 interacts with MDM2 with the PPIase domain, and the interaction between FKBP25 and MDM2 leads to enhanced ubiquitination and degradation of MDM2. Interestingly, the full length, not just the PPIase domain, is required for this activity, suggesting that the N-terminal portion of FKBP25 is critical. Because the N-terminus of FKBP25 contains a helix–loop–helix domain known for mediating protein– protein interactions, this enhancement of ubiquitination of MDM2 is likely through FKBP25 interacting with unknown factors. With knockdown of FKBP25, the expression levels of p53 and its downstream effector p21 are decreased [16], reinforcing the idea that FKBP25 regulates p53 and subsequently p21 expression through controlling the ubiquitination of MDM2. A similar case of FKBPs as coregulators of transcription factors is FKBP38 [17]. FKBP38 was found to interact with PHD2 in a yeast two hybrid screen. PHD2 contains prolyl-4-hydroxylase enzyme activity; when HIF1a is hydroxylated by PHD2, it is degraded. Gene knockdown experiments suggest that FKBP38 associates and promotes the degradation of PHD2, resulting in enhanced expression of HIF1a-target genes [18]. These findings about FKBP25 and FKBP38 demonstrate yet another

mechanism of how FKBPs regulate transcription, which is through modulations of coregulators of transcription factors (Figure 2).

FKBPs as histone chaperones Histone chaperones are histone-binding proteins that regulate nucleosome assembly and disassembly. Fpr3, a yeast FK506-binding protein homologous to FKBP25 [5], binds histone H2B directly [4]. Recently, it was discovered that Fpr3 mediates the prevention of premature adaptation to DNA damage and thus serves to maintain recombination checkpoint activity [19]. In cells lacking Fpr3, a loss of checkpoint function during meiosis was observed, suggesting that the histone-binding activity of Fpr3 is important to DNA damage response. However, whether Fpr3 contains histone chaperone activity remains to be determined. Another FKBP25 homolog in yeast is Fpr4 [5], which was the first FKBP cloned based on its histone chaperone activity and is highly related to Fpr3 [20,21]. Fpr4 forms complexes with histones [21] and interacts with H3 and H4 through its acidic domain located at the N-terminus [22]. In vivo histone chaperone assays demonstrated that the N-terminal part of Fpr4 is required for the chaperone function. Furthermore, FK506, which binds

Figure 2

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FKBPs regulate transcription factor activity by targeting coregulators. MDM2 causes ubiquitination and degradation of p53. Binding of FKBP25 to MDM2 enhances ubiquitination and degradation of MDM2, releasing p53 to activate genes that control the cell cycle. PHD2 causes hydroxylation of HIF1a, which enhances its ubiquitination and degradation. Binding of FKBP38 to PHD2 results in degradation of PHD2, releasing HIF1a to activate genes that control hypoxia response. Question marks denote that unknown factors might participate or facilitate the degradation process of MDM2 and PHD2. www.sciencedirect.com

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to the C-terminal PPIase domain of Fpr4, has no effect on the chaperone activity. These results show that in Fpr4 the histone chaperone activity is independent of the PPIase activity. ChIP assays confirmed that Fpr4 targets to the rDNA locus [20]. However, genetic experiments showed that the N-terminus of Fpr4, which is essential for the histone chaperone activity, is not required for rDNA silencing [20]. These results suggest that Fpr4’s histone chaperone activity is not related to its gene silencing function in the context of regulation of gene expression.

This is further supported with the finding that the PPIase domain of Fpr4 is required for proline isomerization of histone H3 and gene activation [22]. We will further discuss this finding in ‘FKBPs and chromatin structure’ (Figure 3). In plants, an Fpr3/Fpr4 homolog appears to have similar functions. An Arabidopsis FKBP, AtFKBP53, represses rDNA expression through histone chaperone activity and specifically interacts with H3 [23]. The PPIase domain of

Figure 3

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Nuclear functions of FKBPs and mechanistic implication of immunosuppressants. The functions of nuclear FKBPs include direct and indirect regulation of transcription factors, association with histone modifiers such as HDACs, proline isomerization by their PPIase activity, and histone chaperone activities. Whether FKBPs possess direct DNA-binding activity or the ability to regulate DNMTs remains unclear. Therefore, FKBPs target DNA or histones, causing local or global changes at the chromatin level, which in turn affect nuclear events including DNA repair, transcription, and DNA replication that ultimately lead to cancer. Binding of immunosuppressants such as FK506 and rapamycin modulates the functions of FKBPs. Question marks and dash lines indicate events that still require experimental support. Ac, acetyl groups; DNMT, DNA methyltransferase; Me, methyl groups; TX, transcription. Current Opinion in Pharmacology 2011, 11:301–307

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AtFKBP53 is dispensable for histone binding and chaperone activity; however, the unique acidic domain at the N-terminus of AtFKBP53 is responsible for both activities [23]. A recent report studying Chz1 as a chaperone for histone variant H2A.Z discovered an unexpected role of Fpr3 and Fpr4. In a yeast strain deficient for histone chaperones Chz1 and Nap1, Fpr3 and Fpr4 are found in the same glycerol gradient fractions with proteins that bind Htz1, the yeast H2A.Z [24]. This result suggests that Fpr3 and Fpr4 indeed function as histone chaperones, albeit under particular circumstances or as substitute histone chaperones. In summary, recent evidence from yeast to plants suggests that FKBPs might function as histone chaperones, whose activity requires their unique N-terminal acidic domain but not the C-terminal conserved PPIase domain. It is unclear whether such acidic domains exist in mammalian FKBPs. However, mammalian FKBP25 has an N-terminal domain rich in basic residues. This domain can bind nucleolin/C23, and all other mammalian FKBPs lack this N-terminal basic domain [25]. Interestingly, the N-terminal domain of Fpr3 and Fpr4 in yeast has been referred to as the NL (nucleolin-like) domain, raising the possibility that during the diversification of mammalian FKBPs, FKBP25 acquired an ability to regulate nucleosome assembly and disassembly through interacting with nucleolin. Eitoku et al. also suggest that nucleolin and Fpr3 might have similar functional roles in their review about nucleosome dynamics [26].

FKBPs and chromatin structure The first evidence of direct involvement of FKBPs in the regulation of chromatin structure comes with the discovery that FKBP25 associates with histone deacetylase (HDAC) activity [3]. FKBP25 interacts with HDAC1 and HDAC2 with its unique N-terminal portion, whereas the PPIase domain has no effect on FKBP25’s interaction with HDAC1/2 or the associated HDAC activity. Furthermore, FKBP25 forms a stable protein complex and the Nterminal portion of FKBP25 is required for the formation of this protein complex (W.-M. Yang, unpublished data). Interestingly, FKBP25 also interacts with other chromatin-related proteins such as casein kinase (CK) II, nucleolin [25], and high-mobility group (HMB) II protein [27]. Whereas HMB II possesses DNA-binding activity, CKII and nucleolin are involved in the regulation of rDNA transcription. These results suggest that FKBP25 functions as a scaffold using its unique N-terminal domain for protein–protein interaction to form functional protein complexes, such as HDAC complexes, that are important to the structure of chromatin. Since the status of chromatin structure is tightly associated with the regulation of transcription, it is no surprise www.sciencedirect.com

that Fpr4 (the yeast FKBP discussed in ‘FKBPs as histone chaperones’) regulates both chromatin structure and transcription [22]. In vitro peptide binding assays demonstrated that Fpr4 directly binds to the N-terminal tails of H3 and H4. Proline isomerase assays showed that Fpr4 catalyzes isomerization of two amino acids of H3, prolines 30 and 38. Furthermore, using a lose-of-function mutant of Fpr4, the PPIase activity of Fpr4 was demonstrated to be required for the methylation of H3 at lysine 36, which is a chromatin signature for transcriptional elongation. ChIP assays showed that Fpr4 is located on actively transcribed regions, further confirming the role of Fpr4 in the regulation of chromatin structure and transcription. While Fpr4 activates genes transcribed by RNA polymerase (Pol) II [3,22], the PPIase activity of Fpr4 was found to be involved in the silencing of rDNA transcription, which is catalyzed by RNA Pol I [20,24]. These results demonstrate that Fpr4 plays multiple roles and regulates different regions of the chromatin through its ability to modify chromatin. Furthermore, unlike FKBP25, the PPIase activity of Fpr4 appears to be crucial to its ability to regulate chromatin structure and transcription. An interesting study using Fkbp6 deficient mice showed that loss of FKBP6 increases the frequency of abnormal chromosome paring and aberrant localization of gH2AX [28]. This result suggests that certain FKBPs might participate in large-scale chromosome biology.

Conclusion The presence of FKBPs in the nucleus and the elucidation of their functions suggest that the mechanism by which immunosuppressants such as FK506 and rapamycin cure cancer is far from straightforward. In this short review, we tried to understand the role of FKBPs from three perspectives: transcription, histone chaperones, and chromatin structure. It is now clear that FKBP12, FKBP25, FKBP38, FKBP51, and FKBP52 indirectly associate with DNA and affect gene regulation through modulation of DNA-binding transcription factors or proteins that regulate transcription factors. FKBPs, such as yeast Fpr3 and Fpr4, might regulate nucleosome assembly/disassembly and DNA damage responses. Of particular interest is the diverse function of Fpr4. The PPIase activity of Fpr4, which isomerizes prolines of H3, is required for K36 methylation of H3 and gene activation; however, the same PPIase domain is also responsible for silencing at the rDNA locus. Whether histone H3 or H4 is modified at silenced rDNA locus requires further investigation. Furthermore, the biological significance of Fpr4’s histone chaperone activity needs more clarification in the context of chromatin structure. Although Fpr4 and FKBP25 have been placed in the same family tree, they have structurally divergent N-terminal domains. Therefore, the functional human homolog of Fpr4 should be identified and tested. A related issue is that even though Current Opinion in Pharmacology 2011, 11:301–307

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there is no evidence to support direct binding of DNA by FKBPs, research probing whether FKBPs affect DNA methylation is encouraged. In view of recent advances in chromatin biology and epigenetics, we believe further investigation into nuclear events affected by FKBPs will have a valuable impact on our understanding of how FK506 and rapamycin operate as anticancer drugs.

Acknowledgements We thank Feng-Shu Hsieh for critical reading of this manuscript. This work was supported by a grant from the National Health Research Institutes (NHRI-9212SI to W.-M.Y) and by grants from the National Science Council (NSC99-2311-B-005-005-MY3 to W.-M.Y and NSC98-2311-B-468-001-MY3 to Y.-L.Y).

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