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EZH2-Dependent Suppression of a Cellular Senescence Phenotype in Melanoma Cells by Inhibition of P21/CDKN1A Expression

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EZH2-Dependent Suppression of a Cellular Senescence Phenotype in Melanoma Cells by Inhibition of P21/CDKN1A Expression Published OnlineFirst March 7, 2011; DOI: 10.1158/1541-7786.MCR-10-0511 Molecular Cancer Cell Cycle, Cell Death, and Senescence Research EZH2-Dependent Suppression of a Cellular Senescence Phenotype in Melanoma Cells by Inhibition of p21/CDKN1A Expression Tao Fan1, Shunlin Jiang1, Nancy Chung1, Ali Alikhan1, Christina Ni1, Chyi-Chia Richard Lee2, and Thomas J. Hornyak1 Abstract Polycomb group (PcG) proteins such as Enhancer of zeste homolog 2 (EZH2) are epigenetic transcriptional repressors that function through recognition and modification of histone methylation and chromatin structure. Targets of PcG include cell cycle regulatory proteins which govern cell cycle progression and cellular senescence. Senescence is a characteristic of melanocytic nevi, benign melanocytic proliferations that can be precursors of malignant melanoma. In this study, we report that EZH2, which we find absent in melanocytic nevi but expressed in many or most metastatic melanoma cells, functionally suppresses the senescent state in human melanoma cells. EZH2 depletion in melanoma cells inhibits cell proliferation, restores features of a cellular senescence phenotype, and inhibits growth of melanoma xenografts in vivo. p21/CDKN1A is activated upon EZH2 knockdown in a p53- independent manner and contributes substantially to cell cycle arrest and induction of a senescence phenotype. EZH2 depletion removes histone deacetylase 1 (HDAC1) from the CDKN1A transcriptional start site and downstream region, enhancing histone 3 acetylation globally and at CDKN1A. This results in recruitment of RNA polymerase II, leading to p21/CDKN1A activation. Depletion of EZH2 synergistically activates p21/CDKN1A expression in combination with the HDAC inhibitor trichostatin A. Since melanomas often retain wild-type p53 function activating p21, our findings describe a novel mechanism whereby EZH2 activation during tumor progression represses p21, leading to suppression of cellular senescence and enhanced tumorigenicity. Mol Cancer Res; 9(4); 418–29. Ó2011 AACR. Introduction melanocytes. BRAFV600E and activating mutations at codon 61 in NRAS, both found frequently in melanoma Senescence is a cellular stress response resulting in a (7, 8), are also associated with acquired (9) and congenital blockade of cellular proliferation, characteristic morpho- (10) melanocytic nevi, respectively. Both types of nevi are logical changes, and the expression of characteristic mole- benign precursors to melanoma and exhibit characteristics cular markers such as senescence-associated b-galactosidase of senescent cells (5, 11). Progression to melanoma is (SA-b-Gal; 1–3). Overexpression of activated oncogenes associated with loss of the tumor suppressor p16INK4A such as HRASG12V in primary cells triggers oncogene- (5, 12, 13), encoded by the CDKN2A locus, through induced senescence, featuring a cellular phenotype indis- mutation, deletion, or promoter DNA methylation (14). tinguishable from that of cells entering senescence follow- Since senescence is a distinct mechanism of tumor suppres- ing extending in vitro replication (4). Overexpression of sion (2, 15, 16), determining how melanoma cells escape melanoma oncogenes such as BRAFV600E (5) and senescence and devising methods to restore senescence to NRASQ61K (6) provokes oncogene-induced senescence in these cells may be important for developing additional therapeutic options for this malignancy. Polycomb group (PcG) proteins are global repressors of Authors' Affiliations: 1Dermatology Branch and 2Laboratory of Pathology, gene expression effecting transcriptional suppression epi- Center for Cancer Research, National Cancer Institute, NIH, Bethesda, genetically through the formation of polycomb repressor Maryland complexes (PRC), including PRC1 and PRC2 (17, 18). Note: Supplementary data for this article are available at Molecular Cancer Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of Research Online (http://mcr.aacrjournals.org/). PRC2, has a histone methyltransferase activity for histone 3 Corresponding Author: Thomas J. Hornyak, Dermatology Branch, Center for Cancer Research, NCI, NIH, Building 10/12N242, 10 Center Drive, lysine 27 trimethylation (H3K27me3; 19). Generation of Bethesda, MD 20892. Phone: 301-451-1926; Fax: 301-496-5370. E-mail: the H3K27me3 mark by PRC2 establishes a strong repres- [email protected] sive signal for gene expression (20). PcG proteins suppress doi: 10.1158/1541-7786.MCR-10-0511 CDKN2A expression (21). In senescent cells, PcG proteins Ó2011 American Association for Cancer Research. are downregulated or dissociated from the CDKN2A locus 418 Mol Cancer Res; 9(4) April 2011 Downloaded from mcr.aacrjournals.org on September 27, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst March 7, 2011; DOI: 10.1158/1541-7786.MCR-10-0511 EZH2 Suppression of Melanoma Senescence leading to a decreased level of histone H3K27me3 and Cell culture and growth measurement reactivation of INK4/ARF genes (22). Hence, activation of UCD-Mel-N cells were a kind gift from the late Dr. expression of PcG proteins in senescent cells, including Estela Medrano (Baylor College of Medicine, Houston, those of premalignant benign tumors resulting from onco- TX). SK-Mel-30, SK-Mel-103, SK-Mel-119, SK-Mel- gene activation, could contribute to the loss of tumor 147, and SK-Mel-173 cells were graciously provided by suppressor gene activity and drive malignant progression. Dr. Norman Sharpless (University of North Carolina at PcG proteins are overexpressed in various types of human Chapel Hill, Chapel Hill, NC) with the permission of Dr. cancer including prostate cancer and breast cancer and are Alan Houghton (Memorial Sloan-Kettering, New York, functionally important for maintaining the malignant phe- NY). Cells were grown in DMEM (Dulbecco's Modified notypes of those cells (23, 24). However, the function of Eagle's medium, Invitrogen) supplemented with 10% fetal EZH2 in progression from the senescent state and its calf serum (FCS) and were maintained in a humidified mechanisms of action other than CDKN2A suppression incubator at 37 Cand5%CO2. To determine the cell remain unclear. growth rate, cells were plated in 24-well plates (1 Â 104 In this study, we explored the role of EZH2 in senes- cells/well) and transfected either with a control siRNA or cence and tumorigenicity in nevi and melanoma cells. We an siRNA targeting EZH2 (see below). After 24 hours and provide evidence that EZH2 is important to maintain each successive day for 5 consecutive days, cells were resistance to the senescent state in human melanoma cells. trypsinized briefly with 0.05% trypsin/0.02% EDTA We observed a striking difference, on a cell-by-cell basis, and cell numbers were counted. For treatment of cells between the level of EZH2 expressed in acquired mela- with the histone deacetylase inhibitor Trichostatin A nocytic nevi, where it is absent from all or nearly all benign (TSA, Sigma), TSA was dissolved in dimethyl sulfoxide nevus cells, and samples from metastatic melanomas, (DMSO; Sigma). Cells were treated with 1 mmol/L TSA where it is detected in a majority of melanoma cells in or an equal volume of DMSO as a control for 24 hours. most samples studied. Depletion of EZH2 in melanoma For the combined EZH2 siRNA/1 mmol/L TSA treat- cells resulted in a senescent phenotype that was signifi- ment, cells were harvested 3 days following transfection cantly dependent upon activation of p21/CDKN1A with EZH2 siRNA, and TSA was added only for the last expression in a p53-independent manner. Chromatin 24 hours before harvesting. immunoprecipitation (ChIP) analysis shows that EZH2 maintains HDAC1 at the CDKN1A transcriptional start RNA interference site and downstream regions ofthegene.EZH2depletion Cells were seeded and incubated at 37C for 24 hours and removes HDAC1 from these regions, triggering histone transfected with EZH2 siRNA (25) or nonspecific control acetylation and recruitment of RNA polymerase II, result- siRNA (Qiagen, Inc.) using LipofectRNAiMax (Invitrogen) ing in p21/CDKN1A activation. Our findings are con- according to the manufacturer's protocol. For detection of sistent with a model for senescence bypass in melanoma markers of senescence other than SA-b-Gal, a second development whereby EZH2 expression overcomes p53- transfection was performed 3 days after the first transfection dependent senescence to promote malignant progression. prior to fluorescence or immunofluorescence detection of SAHF (senescence-associated heterochromatic foci), a-tubulin distribution, or H3K9me3. To account for Materials and Methods any off-target effects of the siRNA targeting EZH2, key experiments were repeated with a pool of 4 siRNAs (ON- Identification and quantification of EZH2-expressing TARGETplus SMARTpool L-004218-00-0005, Milli- melanocytic cells in vivo pore) targeting different regions of the EZH2 transcript Human samples were collected under the auspices of than the original siRNA used. siRNA sequences are approved human clinical protocols passed by the Institu- described in the Supplementary Information. For sustained tional Review Board of the Intramural Research Program of suppression of EZH2 expression, SMARTvector lentiviral the National Cancer Institute. Relative expression levels of particles (Thermo Scientific) carrying short hairpin RNA EZH2 were determined in melanocytes in normal human (shRNA) targeting EZH2 and a nonspecific shRNA control, skin, benign melanocytic nevi, and metastatic melanoma shN1 (Thermo Scientific,
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