Abstract
Estrogen receptor alpha (ERα) is a ligand-activated nuclear receptor that directs proliferation and differentiation in selected cancer cell types including mammary-derived carcinomas. These master-regulatory functions of ERα require trans-acting elements such as the pioneer factor FOXA1 to establish a genomic landscape conducive to ERα control. Here, we identify the H3K4 methyltransferase KMT2C as necessary for hormone-driven ERα activity and breast cancer proliferation. KMT2C knockdown suppresses estrogen-dependent gene expression and causes H3K4me1 and H3K27ac loss selectively at ERα enhancers. Correspondingly, KMT2C loss impairs estrogen-driven breast cancer proliferation but has no effect on ER- breast cells. Whereas KMT2C loss disrupts estrogen-driven proliferation, it conversely promotes tumor outgrowth under hormone-depleted conditions. In accordance, KMT2C is one of the most frequently mutated genes in ER-positive breast cancer with KMT2C deletion correlating with significantly shorter progression-free survival on anti-estrogen therapy. From a therapeutic standpoint, KMT2C-depleted cells that develop hormone-independence retain their dependence on ERα, displaying ongoing sensitivity to ERα antagonists. We conclude that KMT2C is a key regulator of ERα activity whose loss uncouples breast cancer proliferation from hormone abundance.
Highlights
IntroductionSt. Louis, MO, USA 5 Microchemistry and Proteomics Core Facility, Memorial Sloan
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Medicine, St
We found that both short hairpins, shKMT2C#1 and shKMT2C#2, reduce expression of KMT2C by 60–70% without affecting expression of its most closely related homologs, KMT2A, B, or D (Fig. S2A)
Summary
St. Louis, MO, USA 5 Microchemistry and Proteomics Core Facility, Memorial Sloan. Kettering Cancer Center, New York, USA 6 Computational Biology Program, Memorial Sloan Kettering. Cancer-specific transcriptional programs are foundational to the development of oncogenic phenotypes. Oncogenes such as MYC and BRAF drive unique gene expression signatures that have been shown to be essential for transformation and cancer maintenance [1,2,3,4,5]. Recent large-scale genomic analyses have identified key chromatin modifications permissive of such tissue-specific and cancer-specific transcriptional programs [6, 7]. Among the most significant of these chromatin modifications is methylation at histone H3 lysine 4 (H3K4me), generally marking regions of active and poised transcription. Trimethylation (H3K4me3) of these residues is observed to be more abundant at promoter regions while monomethylation (H3K4me1) is more abundant at enhancer regions [8]
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