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

• Published in: EMBO molecular medicine 2024-01, Vol.16 (1), p.10-39
• Main Authors: Luan, Ruina, He, Mingcong, Li, Hao, Bai, Yu, Wang, Anqi, Sun, Ge, Zhou, Baosheng, Wang, Manlin, Wang, Chunyu, Wang, Shengli, Zeng, Kai, Feng, Jianwei, Lin, Lin, Wei, Yuntao, Kato, Shigeaki, Zhang, Qiang, Zhao, Yue
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; EMBO03; EMBO09; Molecular Medicine
• ISSN: 1757-4684; 1757-4676; 1757-4684
• DOI: 10.1038/s44321-023-00003-z

Endocrine resistance is a crucial challenge in estrogen receptor alpha (ERα)-positive breast cancer (BCa). Aberrant alteration in modulation of E2/ERα signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Herein, we demonstrate that MYSM1 as a deubiquitinase participates in modulating ERα action via histone and non-histone deubiquitination. MYSM1 is involved in maintenance of ERα stability via ERα deubiquitination. MYSM1 regulates relevant histone modifications on cis regulatory elements of ERα-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-ERα axis. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ERα action and provide a potential therapeutic target for endocrine resistance in BCa. Synopsis Co-regulators deeply affect estrogen receptor alpha (ERα)-mediated gene transcription. MYSM1 was identified as an ERα co-activator that participates in ERα signaling regulation and is antagonistic to endocrine sensitivity in ERα-positive breast cancer (BCa). MYSM1 maintains ERα stability through its deubiquitinase catalytic domain MPN. MYSM1 forms a histone-modifying complex with HATs at ERα-target promoters to epigenetically induce ERα-mediated gene transcription. MYSM1 promotes cell growth and decreases antiestrogen sensitivity in BCa through ERα 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 (ERα)-mediated gene transcription. MYSM1 was identified as an ERα co-activator that participates in ERα signaling regulation and is antagonistic to endocrine sensitivity in ERα-positive breast cancer (BCa).