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?)-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.
Mesh Terms:
Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Estrogen Receptor Modulators, Estrogen Receptor alpha, Female, Gene Expression Regulation, Neoplastic, Histones, Humans, Trans-Activators, Ubiquitin-Specific Proteases
EMBO Mol Med
Date: Jan. 01, 2024
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