MYSM1 acts as a novel co-activator of ERa to confer antiestrogen resistance in breast cancer

Endocrine resistance is a crucial challenge in estrogen receptor alpha (ER)-positive breast cancer (BCa). Aberrant alteration in modulation of E2/ER signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Herein, we demonstrate that MYSM1 as a deubiquitinase participates in modulating ER action via histone and non-histone deubiquitination. MYSM1 is involved in maintenance of ER stability via ER deubiquitination. MYSM1 regulates relevant histone modifications on cis regulatory elements of ER-regulated genes, facilitating chromatin decondensation. MYSM1 is highly expressed in clinical BCa samples. MYSM1 depletion attenuates BCa-derived cell growth in xenograft models and 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-ER axis. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ERaction and provide a potential therapeutic target for endocrine resistance in BCa.