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

Endocrine resistance is a crucial challenge in estrogen receptor alpha (ER alpha)-positive breast cancer (BCa). Aberrant alteration in modulation of E2/ER alpha 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 alpha action via histone and non-histone deubiquitination. MYSM1 is involved in maintenance of ER alpha stability via ER alpha deubiquitination. MYSM1 regulates relevant histone modifications on cis regulatory elements of ER alpha-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 alpha axis. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ER alpha action and provide a potential therapeutic target for endocrine resistance in BCa. Co-regulators deeply affect estrogen receptor alpha (ER alpha)-mediated gene transcription. MYSM1 was identified as an ER alpha co-activator that participates in ER alpha signaling regulation and is antagonistic to endocrine sensitivity in ER alpha-positive breast cancer (BCa).MYSM1 maintains ER alpha stability through its deubiquitinase catalytic domain MPN. MYSM1 forms a histone-modifying complex with HATs at ER alpha-target promoters to epigenetically induce ER alpha-mediated gene transcription. MYSM1 promotes cell growth and decreases antiestrogen sensitivity in BCa through ER alpha signaling. Imatinib was found through a virtual screen to potentially interact with the MPN domain of MYSM1 and inhibit its activity. Higher MYSM1 expression is associated with a poorer overall survival in BCa specimens. Co-regulators deeply affect estrogen receptor alpha (ER alpha)-mediated gene transcription. MYSM1 was identified as an ER alpha co-activator that participates in ER alpha signaling regulation and is antagonistic to endocrine sensitivity in ER alpha-positive breast cancer (BCa).