Carcinogenesis is a multistep process emanating from the accumulation of genetic and epigenetic alterations in genes that regulate cell proliferation, growth, differentiation, adhesion, migration, angiogenesis, and apoptosis. Modulation of gene expression relies on the dynamic balance and spatiotemporal control of specific transcription factors that interact with the basal transcriptional apparatus as well as with transcriptional coregulators (corepressors and coactivators), resulting in a multicomplex protein network.1, 2 Transcriptional coregulators contribute to the accuracy of this circuitry and can function as (or cross-talk with) histone-modifying enzymes to control epigenetic events; modify chromatin structure; and, thus, regulate gene expression patterns.3 Specifically, corepressor protein complexes can mediate enzymatic repression of gene transcription through multiple biochemical mechanisms.3, 4
Diverse corepressor complexes have been identified. These include nuclear receptor corepressor 1 (NCoR1), NCoR2/silencing mediator for retinoid and thyroid hormone receptors (NCoR2/SMRT), C-terminal–binding proteins (CTBP1, CTBP2), RE1-silencing transcription factor (REST)/neural-restrictive silencing factor (REST/NRSF), Rest corepressor (RCOR/CoREST), runt-related transcription factor (RUNX), breast cancer metastasis suppressor 1 (BRMS1), BTG3-associated nuclear protein/scaffold-matrix–associated region 1-binding protein (BANP/SMAR1), zinc-finger and breast cancer type 1 susceptibility protein (BRCA1)-interacting protein with a Kruppel-associated box (KRAB) zinc finger domain 1 (ZBRK1/ZNF350), nuclear receptor-interacting protein 1 (NRIP1/RIP140), nucleosome remodeling and histone deacetylase (NURD), and Swi-independent 3 (SIN3).
Mechanistically, it is suggested that transcriptional corepressors bind to nuclear receptors in the absence of their ligand; whereas the presence of ligand can change the receptor configuration, favoring binding to coactivators, thus stimulating gene transcription.5 The NCoR1-SMRT complex, the SIN3 complex, the corepressor Alien, and orphan nuclear receptors are paradigms of this mechanism, acting as constitutive repressors.5 Alternatively, a “competitive” dynamic balance between coactivators and corepressors is proposed as another putative mechanism of transcription regulation, with the release of a corepressor and the binding of a coactivator marking a new transcription cycle. A unique category of corepressors, namely, receptor-interacting protein 140 (RIP140) and ligand-dependent corepressor (LCoR), manifests agonist/antagonist bound-dependent corepression.5, 6 Overall, cells can modulate corepressor complexes in a multilevel manner to achieve a high degree of transcriptional fine-tuning. Apart from ligand-binding–induced, conformational changes resulting in the dissociation of corepressors, such modulation also can be achieved through post-translational modifications followed by nuclear export and/or degradation of the corepressor.7 Therefore, qualitative and quantitative changes of corepressors can play a key role in the transcriptional output of both normal and tumor cells. The functional role of transcriptional corepressors can vary in a temporal and spatial manner (“pleiotropic activity”), participating in normal cell differentiation and tissue homeostasis as well as in cell transformation and tumor progression (Table 1).4, 8-30 In that these intricate protein complexes can affect oncogenic signal-transduction cascades, they constitute potential regulators of self-sustained cell proliferation, resistance to apoptosis, unrestrained migration, angiogenesis, and metastasis.
|Corepressor Complex||Molecular Interactions||Functions and Roles||Implication in Cancer Type||References|
|NCoR1, NCoR2/SMRT||NRs, NF-κB, AP-1, MYOD, ETO, CBF, TFIIB, MAD/MXI||HDAC: multiple roles in a context-specific manner||Bladder, breast, prostate, colorectal, endometrial, glioma, leukemia||Perissi 2010,4 Battaglia 2010,8 Liu 20079|
|CTBP1/2||ER, INK4a/b, Bax, CoREST, p21, PERP, PTEN, E-cadherin, Noxa||HDAC, HDEM: promotes cell proliferation, invasiveness/migration, EMT; antagonizes apoptosis||Breast, colorectal, hepatocellular||Battaglia 2010,8 Straza 2010,10 Chinnadurai 2009,11 Chen 2008,12 Stossi 200913|
|RUNX1/2/3||CBF, TLE1, NRs, AP-1, HDAC3, MYST4, STUB1, SMAD1/3, SUV39H1||Transcription factors: RUNX1, hematopoietic cell differentiation; RUNX2, bone development; RUNX3, T-cell regulation, neuronal differentiation; role in mitosis||Leukemia, lymphoma, breast, gastric, thyroid, prostate, embryonal carcinoma||Battaglia 2010,8 Chua 2009,14 Chuang 2012,15 Niu 201216|
|CoREST||Rest, CTBP, SWI/SNF, ZNF217||HDAC, HDEM: multiple roles in a context-specific manner||Breast, prostate, colorectal||Battaglia 2010,8 Lakowski 2006,17 Thillainadesan 200818|
|BRMS1||SIN3a HDAC chromatin remodeling complexes (e.g. ARID4A, RBP-1)||HDAC (mSin3a family): metastasis suppressor; apoptosis inducer; NF-κB/EGFR down-regulation; miRNA regulation||Breast, melanoma||Battaglia 2010,8 Liu 2006,19 Edmonds 2009,20 Metge 2008,21 Meehan 2004,22 Hurst & Welch 201123|
|NURD||ER, AP-1, TWIST, SNAIL, FOG1, IKAROS, Rb, BCL6, BCL11B, PML–RARα, INK4, NAB2, ZIP, LSD1, MYC, BRCA, HIF1a, HER2, PAX, p53||HDAC, ATP-dependent chromatin remodeling: tumor promoter or suppressor in a context-specific manner; hematopoietic stem cell differentiation; role in cell cycle, genomic stability, EMT, metastasis||Breast, colorectal, gastric, esophageal, endometrial, pancreatic, ovarian, nonsmall-cell lung, prostate, hepatocellular, diffuse large B-cell lymphoma, leukemia||Lay & Wade 2011,24 Manavathi 2007,25 Wang 2009,26 Ramierz 2010,27 Kai 2010,28 Hsia 2020,29 Fujita 200330|
A volume of data has documented alterations in the structure, expression level, and/or function of transcriptional corepressors in a broad array of human malignancies.8, 31, 32 It becomes evident that corepressors may function as rational therapeutic targets and/or potential biomarkers of response to selective chemotherapy regimens. Here, we present selected examples of this relatively novel and challenging therapeutic concept.
Transcriptional Corepressors: Paradigms of Potential Tumor Targeting
Nuclear receptor corepressor 1 and nuclear receptor corepressor 2/silencing mediator for retinoid and thyroid hormone receptors
NCoR1 and NcoR2 are archetype transcriptional corepressors, and their structure and role have been well described.33-36 Tumorigenic roles have been recognized in acute promyelocytic leukemia (APL), which results in fusion oncoproteins (promyelocytic leukemia [PML]-retinoic acid receptor alpha [RARα] or PML zinc finger [PLZF]-RARα) that sustain NCoR1 interactions, leading to a condensed structure of chromatin and, hence, preventing RARα-mediated cell differentiation.37 In contrast to PML-RARα, PLZF fusion protein is resistant to pharmacologic doses of retinoic acid; this resistance might be overcome by the addition of histone deacetylase (HDAC) inhibitors. In acute myeloid leukemia (AML), the AML1-821 corepressor (ETO) fusion oncoprotein can recruit NCoR1, hindering transcription regulation.38 The revelation of a functional role for NCoR1 in leukemia illustrates the importance of transcriptional corepressors in mediating tumorigenic actions and provides a rational for HDAC targeting. For example, HDAC inhibitors resulted in myeloid cell differentiation in vitro, corresponding to increased histone 3 and histone 4 acetylation; however, they did not alter ncor1 or ncor2 gene expression.39
Expression profiling of solid tumors has revealed alterations in NCoR1/NCoR2 expression and localization.40-43 These alterations may have prognostic value and/or may predict response to specific therapeutic interventions, such as response to tamoxifen in estrogen receptor (ER)-positive breast cancer. In colorectal cancer, which is not considered hormone-dependent, post-translational modifications of NCoR1 and NCoR2 can affect their cytoplasmic localization, hindering β-catenin binding to lymphoid enhancer factor/T-cell factor (LEF/TCF) target genes and promoting TCF4 transcriptional repression.44, 45 It is noteworthy that corepressor changes can occur within the tumor cells and/or in the surrounding microenvironment, which appears to exert an important role in tumor initiation and progression. There is considerable uncertainty in the timing and degree of corepressor alteration with regard to tumor development; however, thorough understanding of such molecular interplays can provide a platform for testing novel therapeutic regimens with or without additional hormone and/or biologic treatments.
C-terminal–binding proteins 1 and 2
CTBP1 and CTBP2 are 2 similar, highly conserved corepressors that have been linked to cancer progression and can be regarded as putative therapeutic targets.10, 11 CTBPs may promote cell proliferation, epithelial-mesenchymal transition (EMT), and invasiveness, although they may inhibit apoptosis through suppression of INK4 (cyclin-dependent kinase inhibitor 2A gene) cell-cycle control proapoptotic genes11; this appears to be relevant in hepatocellular carcinoma.12 The activities of CTBP1 and CTBP2 are context-dependent and time-dependent. CTBP1 is associated with ERα trans-repression, whereas its deregulation can deform normal transcriptional activity in breast cancer cells.13, 46 In colorectal cancer, CTBP up-regulation has been recognized as an event downstream of adenomatous polyposis coli (APC) loss and has been correlated with alternative reading frame (ARF) loss.47 However, low CTBP levels in melanoma allow up-regulation of LEF/TCF-related genes, contributing to invasion.48 The compound 4 methylthio-2-oxobutyric acid (MTOB) can bind to CTBP, triggering conformational changes that result in CTBP dislocation from target-gene promoters.10 Alternatively, reduction of nicotinamide adenine dinucleotide (NADH) levels with antioxidants may distort CTBP binding to its interacting proteins.8, 49
Rest corepressor and runt-related transcription factor
CoREST forms a complex with REST to repress target-gene transcription and acts as a docking platform for the assemblage of HDAC1/HDAC2, BRCA2-associated factor 35 (BRAF35), BRAF35-HDAC complex protein (BHC80), and lysine-specific histone demethylase 1 (LSD1).17 LSD1 is up-regulated in a gamut of solid tumors and has been associated with a poor prognosis.50-52 However, abnormal epigenetic silencing of tumor suppressor genes by LSD1 has been demonstrated in colorectal cancer cell lines.53 LSD1 inhibition, combined with DNA methyltransferase inhibition, may re-establish the expression of repressed genes. CoREST can also form a larger complex with ZNF217, a candidate oncogene in breast cancer; this has been correlated with loss of transforming growth factor-beta (TGF-β) responsiveness and repression of tumor suppressor genes, such as p15ink4b.18 CoREST can also participate in complex formation with switch/sucrose nonfermentable (SWI/SNF) and CTBP, resulting in tumorigenic activity.8, 54
Transcription factors of the RUNX family were identified in embryonal carcinoma cells after RAR-induced differentiation. The oncogenic capacity of RUNX2 was unveiled by the creation of a transgenic mouse with runx2 under the control of cd2 promoter, which resulted in the perturbation of thymocyte development and spontaneous lymphoma.55 Augmented RUNX2 expression levels have been noted in breast cancer cell lines; and RUNX2 may be implicated in bone metastasis, reflecting its role in bone biology.56 RUNX2 seems to be downstream of Wnt and forms a network that is pertinent in prostate cancer cell growth, rendering it a potential therapeutic target.8, 14, 57
Breast cancer metastasis suppressor 1 and nucleosome remodeling and histone deacetylase
BRMS1 interacts with several proteins, such as retinoblastoma-binding protein-1 (RBP-1), the mammalian SIN3-HDAC complex, and heat-shock protein 90 (Hsp90). BRMS1 complexes can suppress nuclear factor-kappaB (NF-κB) activity through the inhibition of inhibitor of NF-κB-alpha (IκBα) phosphorylation and subsequent degradation.58 BRMS1 contributes to direct suppression of the transcription factor p65 (RelA)/p65 subunit of NF-κB through HDAC1-catalyzed deacetylation, whereas BRMS1 knockdown permits the recruitment of acetylated RelA/p65 to NF-κB–dependent antiapoptotic target genes.19 In addition, BRMS1 can regulate the levels of microRNAs (miRNAs) that play a role in metastasis.8, 20
The NURD complex is an ATP-dependent chromatin remodeling complex that can recruit HDAC1, HDAC2, and LSD1. It is involved in the preservation of DNA integrity and can function either as a tumor promoter or a tumor suppressor in a context-specific manner.24, 25 It is suggested to play a role in tumor initiation, progression, and invasion. NURD complexes inhibit p53 through deacetylation interactions with snail zinc finger protein (SNAIL) and twist-related protein (TWIST) during EMT. Metastasis-associated protein 1 (MTA1), a NURD component, can be up-regulated by the oncogene myc (v-myc-myelocytomatosis viral oncogene homolog [avian]), correlating with invasion and a poor outcome in a wide spectrum of tumors.24, 25 In breast cancer, human epidermal growth factor receptor 2 (HER2) signaling up-regulates MTA1, whereas MTA1 and MTA2 inhibit estrogen activity. MTA3, another NURD component, competes with MTA1, inhibits EMT, and inhibits TGF-β and mitogen-activated protein kinase (MAPK) tumorigenic signaling.24-26 In APL, NURD is recruited by the fusion protein PML-RARα, impairing cell differentiation.27 In addition, resveratrol (3,4′,5-trihydroxystilbene; a natural polyphenolic compound) activates p53 in prostate cancer cells by MTA down-regulation and NURD destabilization, an effect that is enhanced by HDAC inhibition.28 A low-molecular-mass compound that mimics the function of an MTA1 splice variant, which regulates estrogen nuclear localization, has demonstrated anticancer effects in an in vivo model.29