MYSM1 acts as a novel co-activator of ERα to confer antiestrogen resistance in breast cancer
- Resource Type
- Original Paper
- 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
- Source
- EMBO Molecular Medicine. 16(1):10-39
- Subject
- Breast Cancer
Epigenetic Modifier
Estrogen Receptor α
MYSM1
Protein Deubiquitination
- Language
- English
- ISSN
- 1757-4684
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).