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SUPT6H Controls Estrogen Receptor Activity and Cellular Differentiation by Multiple Epigenomic Mechanisms

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SUPT6H Controls Estrogen Receptor Activity and Cellular Differentiation by Multiple Epigenomic Mechanisms Oncogene (2015) 34, 465–473 & 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc ORIGINAL ARTICLE SUPT6H controls estrogen receptor activity and cellular differentiation by multiple epigenomic mechanisms U Bedi1,2, AH Scheel3,4, M Hennion2, Y Begus-Nahrmann2,JRu¨ schoff3 and SA Johnsen1,2 The estrogen receptor alpha (ERa) is the central transcriptional regulator of ductal mammary epithelial lineage specification and is an important prognostic marker in human breast cancer. Although antiestrogen therapies are initially highly effective at treating ERa-positive tumors, a large number of tumors progress to a refractory, more poorly differentiated phenotype accompanied by reduced survival. A better understanding of the molecular mechanisms involved in the progression from estrogen-dependent to hormone-resistant breast cancer may uncover new targets for treatment and the discovery of new predictive markers. Recent studies have uncovered an important role for transcriptional elongation and chromatin modifications in controlling ERa activity and estrogen responsiveness. The human Suppressor of Ty Homologue-6 (SUPT6H) is a histone chaperone that links transcriptional elongation to changes in chromatin structure. We show that SUPT6H is required for estrogen-regulated transcription and the maintenance of chromatin structure in breast cancer cells, possibly in part through interaction with RNF40 and regulation of histone H2B monoubiquitination (H2Bub1). Moreover, we demonstrate that SUPT6H protein levels decrease with malignancy in breast cancer. Consistently, SUPT6H, similar to H2Bub1, is required for cellular differentiation and suppression of the repressive histone mark H3K27me3 on lineage-specific genes. Together, these data identify SUPT6H as a new epigenetic regulator of ERa activity and cellular differentiation. Oncogene (2015) 34, 465–473; doi:10.1038/onc.2013.558; published online 20 January 2014 Keywords: estrogen receptor; breast cancer; differentiation; chromatin INTRODUCTION enzymes, changes in histone modifications, chromatin remodeling The estrogen receptor a (ERa) is one of the key transcriptional and significant changes in overall chromatin organization.10–13 regulators of proliferation and differentiation in the mammary These changes appear to be required for the efficient expression epithelium.1 Approximately two-thirds of human breast cancers of estrogen-regulated genes and may represent new potential express ERa.ERa expression is associated with a more therapeutic targets.14 In previous studies, we uncovered a tumor differentiated luminal tumor phenotype and overall better suppressor function for H2Bub115–17 where its levels decrease patient survival compared with ERa-negative tumors.2,3 Thus, during the malignant progression of breast cancer. Interestingly, ERa expression is an important prognostic marker and is although H2Bub1 is required for ERa-regulated gene transcription, predictive for tumor response to antiestrogen treatment. Despite instead of leading to impaired cell proliferation, a loss of H2Bub1 an initial positive response, roughly one-third of ERa-positive instead led to the estrogen-independent growth of ERa-positive tumors becomes refractory to antihormone therapy and develops MCF7 breast cancer cells,15 possibly implicating a loss of H2Bub1 estrogen-independence. Therefore, an increased understanding in the transition from an estrogen-dependent to hormone- of the molecular mechanisms controlling ERa-mediated tran- independent growth of breast cancer. scriptional regulation may help to uncover new molecular targets Consistent with the inverse correlation between H2Bub1 and which may be utilized to more effectively treat and eradicate differentiation status in breast cancer, H2Bub1 levels increase ERa-positive tumors.4 during the differentiation of various types of somatic and Recent studies have demonstrated that one of the essential pluripotent stem cells.18–20 Furthermore, a loss of H2Bub1 results transcriptional regulatory steps controlled by ERa is transcriptional in impaired differentiation in diverse stem cell systems and elongation.5 ERa interacts with the Positive Transcription organisms indicating that H2Bub1 levels are intimately connected Elongation Factor-b complex6 that promotes transcriptional to differentiation status in both normal and tumor cells. elongation in part by phosphorylating Ser2 (pSer2) within the Mechanistically, H2Bub1 appears to be associated with tran- carboxy-terminal domain of RNA Polymerase II (RNAPII).7 HEXIM1, scriptional elongation where it is localized within the transcribed a negative regulator of Positive Transcription Elongation Factor-b region of active genes and its presence is associated with gene activity also interacts with ERa8 and its overexpression leads to a expression levels.21 Consistently, H2B monoubiquitination is tamoxifen-resistant phenotype in breast cancer cells.9 dependent upon the activity of Positive Transcription Elongation ERa-regulated transcription is a highly dynamic process which is Factor-b and phosphorylation of Ser2,22,23 where the obligate associated with the recruitment of multiple histone-modifying heterodimeric H2B ubiquitin ligase complex RNF20/40 is linked to 1Center of Experimental Medicine, Department of Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; 2Institute of Molecular Oncology, University Medical Center Go¨ttingen, Go¨ttingen, Germany; 3Institute of Pathology Nordhessen, Kassel, Germany and 4Center for Pathology and Forensic Medicine, Department of Pathology, University Medical Center Go¨ttingen, Go¨ttingen, Germany. Correspondence: Professor SA Johnsen, Center of Experimental Medicine, Department of Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg 20251, Germany. E-mail: sjohnsen@alumni.mayo.edu Received 15 July 2013; revised 21 November 2013; accepted 22 November 2013; published online 20 January 2014 SUPT6H controls estrogen receptor activity and cellular differentiation U Bedi et al 466 elongating RNAPII via the WW domain containing adapter with RESULTS coiled-coil (WAC) protein that binds directly to pSer2.24 Similar to SUPT6H is required for ERa activity WAC, the histone chaperone Suppressor of Ty Homologue-6 Given the importance of transcriptional elongation in the (SUPT6H) binds to the elongating Ser2 phosphorylated form of 25,26 regulation of ERa activity, we hypothesized that the histone RNAPII. As the yeast Suppressor of Ty-6 (Spt6) protein was chaperone and transcriptional elongation regulatory protein, shown to be required for transcriptional regulation by human ERa 27 SUPT6H may also be required for estrogen-regulated transcription. in yeast, we hypothesized that SUPT6H may also regulate ERa In order to test this hypothesis, we compared the effects of small activity and influence H2Bub1 during cellular differentiation and interfering RNA-mediated knockdown of SUPT6H to those of the tumor progression. In order to address this hypothesis, we pure ERa antagonist, ICI 1 82 780 on the induction of several investigated the function of SUPT6H in ERa-positive MCF7 and estrogen-regulated genes in the ERa-positive luminal breast T47D breast cancer cells and demonstrate that SUPT6H is required cancer cells, MCF7 and T47D. Indeed, the induction of the for estrogen-regulated gene transcription and the maintenance of investigated direct ERa target genes (CXCL12, GREB1 and PGR) was chromatin structure. We show that these effects are linked to similarly decreased following SUPT6H knockdown or ICI 1 82 780 H2Bub1, where SUPT6H and H2Bub1 levels correlate with the treatment in both the cell lines (Figures 1a and b) while the differentiation status of primary breast tumors and similarly expression of TTP and DSP and ERa expression were not affected regulate cellular differentiation via removal of the repressive by either SUPT6H knockdown or ICI 1 82 780 treatment mark H3K27me3. These findings identify SUPT6H as a central (Supplementary Figures S1a–d). Furthermore, since SUPT6H regulator of ERa activity and cellular differentiation status and displays histone chaperone activity and may therefore promote suggest that alterations affecting transcriptional elongation and the opening of chromatin and binding of ERa, we next tested associated changes in chromatin structure may have a central role whether its depletion affects ERa recruitment to chromatin at in malignant progression. Estrogen Response Elements (ERE) on two well characterized Figure 1. SUPT6H knockdown decreases estrogen-induced gene expression by reducing ERa recruitment to target genes. (a, b) MCF7 and T47D cells were transfected with either control or SUPT6H small interfering RNA (siRNAs) or treated with ICI 1 82 780, grown for 24 h before switching to hormone-deprived medium and grown for another 24 h. Cells were then stimulated with 10 nmol/l 17b-estradiol (E2) for 6 h and the expression levels of CXCL12, GREB1, PGR and SUPT6H were analyzed by quantitative PCR (qPCR). Gene expression levels were normalized to 18S ribosomal RNA, graphed relative to the control sample and expressed as ‘Relative mRNA Expression’; mean values þ s.d., n ¼ 3. (c, d) Decreased ERa and SUPT6H recruitment to distal EREs of GREB1 and PGR upon SUPT6H knockdown. MCF7 cells were transfected and cultured as in (a), except that cells were stimulated with 10 nmol/l 17b-estradiol (E2) for 2 h. ChIP samples were normalized to input samples and expressed as ‘% Input’; mean values þ s.d., n ¼ 3. The
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