Nuclear Receptor Coregulators in Cancer Biology Bert W
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Published OnlineFirst October 20, 2009; DOI: 10.1158/0008-5472.CAN-09-2223 Review Nuclear Receptor Coregulators in Cancer Biology Bert W. O'Malley1 and Rakesh Kumar2 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas and 2Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, George Washington University Medical Center, Washington, District of Columbia Abstract Coactivator Mechanisms Coregulators (coactivators and corepressors) occupy the In the steady-state cell, coregulators exist and function in large driving seat for actions of all nuclear receptors, and conse- multiprotein complexes (3). For example, coactivator complexes quently, selective receptor modulator drugs. The potency are recruited by NRs to target genes in an ordered sequence to pro- and selectivity for subreactions of transcription reside in vide the many enzyme capacities required for transcription (5). the coactivators, and thus, they are critically important for Subreactions of transcription mediated by coactivator complexes tissue-selective gene function. Each tissue has a “quantitative include chromatin modification and remodeling, initiation of tran- finger print” of coactivators based on its relative inherited scription, elongation of RNA chains, mRNA splicing, and even, pro- concentrations of these molecules. When the cellular concen- teolyic termination of the transcriptional response. Surprisingly, tration of a coactivator is altered, genetic dysfunction usually recent reports show that coactivators can influence cellular reac- leads to a pathologic outcome. For example, many cancers tions outside the nucleus such as mRNA translation, mitochondrial overexpress “growth coactivators.” In this way, the cancer function, and motility (6). The expanding importance of coactiva- cell can hijack these coactivator molecules to drive prolifer- tors (and corepressors) to mammalian cancer merits reflection on ation and metastasis. The present review contains summaries selected historical advances that have promoted the development of selective coactivators and corepressors that have been of this field. In the following mini-review, there is insufficient space demonstrated to play important roles in the malignant pro- to discuss all of the numerous excellent studies that substantiate cess and emphasizes their importance for future therapeutic the importance of coregulators to cancer, so only a limited number interventions. [Cancer Res 2009;69(21):8217–22] of selected cases will be used to illustrate their relevance to cancer biology. It has been only 12 years since the first nuclear receptor coacti- When considering the plethora of functions that NRs play in tis- vator, SRC-1, was cloned and discovered to be a new form of tran- sues such as breast, ovary, prostate, intestine, pancreas, and lungs, scription factor (TF) that, rather than binding to DNA, binds to and the interest in the cancers of these organs, we anticipate a rel- nuclear receptors (NR) and mediates the transcriptional potency atively large number of coregulators to be involved in cancer. How- of NRs (1, 2). The NR coactivators belong to a class of molecules ever, this spectrum of tissues indicates that the oncogenic or generally termed coregulators (2). We define coactivators as mole- tumor suppressive activities of coregulators play key roles in di- cules that are recruited by DNA-binding TFs to enhance transcrip- verse tissues, well beyond the classic endocrine targets of NRs. tion, and corepressors as molecules that are recruited by TFs to The concentrations of coactivators and corepressors in cells are repress transcription. Current evidence indicates that this opera- critical to their functional potential. Indeed, the cellular levels of coac- tional definition can be modified by gene and cell and signaling tivators are frequently regulated by altering their post-translational context for any one coregulator. Our current understanding is that degradation rates (7). A high cellular concentration of a coactivator NRs search out the target genes to be regulated by binding to spe- will lead to an amplified signal within a downstream TF action cific DNA sequences (or other TFs at such sequences) termed pathway, as well as a more rapid response to environmental sig- NR-response elements; the second job of NRs is to recruit the core- nals. However, available data from our laboratories and a variety gulators that carry out all of the subsequent biochemical reactions of other sources suggest that the key to understanding the true required for induction or repression of gene transcriptions. In fact, diversity of coregulator functions lies in first understanding the most coregulators are either enzymes needed for gene expression, or surprisingly extensive “post-translational coding” that has been they regulate the enzymatic activities of other co-coregulators that discovered to exist in the coregulator proteins (8). In the case of a are present in the high molecular weight transcriptional complexes coregulator, it has been observed that a combination of such post- at the gene. Over the past decade, the mechanistic importance of translational modifications (PTM) can lead to functionally distinct coregulators has expanded logarithmically, and we now realize that activities for the same primary sequence protein. The “differential- they are responsible for virtually “all” of the reactions needed for ly coded” coactivator is now predisposed to form different multi- control of TF-dependent gene expression (3, 4). meric coactivator complexes, and thereby, to interact with distinct genes and to do different compartmental functions in a cell. For example, more than 40 separate modifications of the SRC-3 coactivator have been determined to date (9). These include phosphorylations, methylations, acetylations, ubiquitinations, and SUMOylations. This plethora of 40 PTMs creates an enormous “ ” 40 Requests for reprints: Bert W. O'Malley, BCM502, Room M613, One Baylor Plaza, combinatorial potential of (2) (9). The vast majority of this PTM Houston, TX 77030; or Rakesh Kumar, 2300 Eye Street, NW, Suite 530, Washington, DC potential complexity likely is never actually used in a given cell. 20037. ©2009 American Association for Cancer Research. Nevertheless, because every single PTM can result in a protein doi:10.1158/0008-5472.CAN-09-2223 with some altered function, it is an inescapable conclusion that www.aacrjournals.org 8217 Cancer Res 2009;69: (21). November 1, 2009 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst October 20, 2009; DOI: 10.1158/0008-5472.CAN-09-2223 Cancer Research multiple combinations of PTMs can bestow a huge array of dis- Because the course of polyubiquitinylation is processive during tinct functions to any one coregulator protein. the transcriptional activation of TFs, this phosphorylation- dependent ubiquitinylation functions as a transcriptional time clock to first initiate coactivator activation, and then ultimately, SRC-3 Coactivator Is an Oncogene and a Target for to limit the lifetime of the PTM-activated coactivator (28). Epigenetic Signals PTMs of SRC-3 influence its structural association dynamics SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM1/NCOA3 is the third with other co-coactivators. CARM1 methylates SRC-3 and dissoci- member of the SRC/p160 coactivator family, and because it is ates it from its active coactivator complex (6). Peptidyl-prolyl isom- the most studied of NR coactivators, it serves as a prototype exam- erase 1 (Pin1) catalyzes the cis-trans isomerization of proline ple for defining the range of mechanisms and functions of such residues adjacent to phosphorylated serine/threonine-P bonds to molecules. This gene was characterized as AIB1 (Amplified in induce conformational changes in the SRC-3 protein and enhance breast cancer-1) and originally reported to be amplified in approx- the interactions between SRC-3 and other coactivators such as imately 10% and overexpressed in 64% of primary breast tumor CBP/p300 (29, 30). Experimentally induced down-regulation of cells (10). It was subsequently found to be amplified and over- Pin1 in breast cancer cells was shown to reduce ligand-dependent expressed in numerous other human cancers such as bladder, na- transcription by NRs and Pin1 overexpression has been implicated sopharyngeal, endometrial, prostate, etc. Clinical studies in breast in oncogenesis (31). cancer patients show that overexpression of SRC-3 correlates with tamoxifen resistance, p53- and HER2-expression status, and leads to markedly negative clinical outcomes (11–15). Metastatic Tumor Antigen 1: A Coregulator with Dual The oncogenic potential for SRC-3 is substantiated by studies in Function transgenic mice that overexpress SRC-3 and develop spontaneous −/− Metastatic tumor antigen 1 (MTA1) was initially identified as an malignant mammary tumors (16). In contrast, SRC-3 mice are upregulated gene through differential screening of a cDNA library resistant to chemical carcinogen-induced and viral-induced mam- −/− from rat metastatic breast tumors (32). Subsequent studies found a mary tumorigenesis (17, 18). SRC-3 mice also show resistance to widespread upregulation of MTA1 in multiple human tumors, in- induced prostate cancer progression (19). These results are consis- cluding breast, prostate, colorectal, gastric, esophageal, ovarian, tent with the idea that SRC-3 is a potentially powerful oncogene. In pancreatic, non-small