MYSM1 acts as a novel co-activator of ERa via histone and non-histone deubiquitination to confer antiestrogen resistance in breast cancer
Endocrine resistance is a crucial challenge in estrogen receptor alpha (ERa)-positive breast cancer (BCa). Aberrant alteration in modulation of E2/ERa signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Herein, we demonstrate that MYSM1 as a deubiquitinase participates in modulating ERa action via histone and non-histone deubiquitination. MYSM1 is involved in maintenance of ERa stability via ERa deubiquitination. Silencing MYSM1 induces enhancement of histone H2A ubiquitination as well as reduction of histone H3K4me3, H3K9ac and H3K27ac levels at cis regulatory elements on promoter of ERa-regulated genes. ChIP-seq analysis indicate that the half-EREs are the significant enrichment sites for MYSM1 on ERa-regulated genes. MYSM1 depletion attenuates cell growth in BCa-derived cell lines and xenograft models. Knockdown of MYSM1 increases the sensitivity of antiestrogen agents in BCa cells. A virtual screen shows that the small molecule Imatinib could potentially interact with catalytic MPN domain of MYSM1 to inhibit BCa cell growth via MYSM1-ERa axis. MYSM1 is highly expressed in clinical BCa samples, especially in aromatase inhibitor (AI) non-responsive tissues. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ERa action and provide a potential therapeutic target for endocrine resistance in BCa. Overall design: MCF7 cells were treated with estrogen(E2)  and equal EtOH for 1 hour