MYSM1 co-activates ERα action via histone and non-histone deubiquitination to confer antiestrogen resistance in breast cancer

Zhao, Y.; Luan, R.; Sun, G.; Zhou, B.; Wang, M.; Bai, Y.; Wang, C.; Wang, S.; Zeng, K.; Feng, J.; He, M.; Lin, L.; Wei, Y.; Zhang, Q.

doi:10.1101/2022.12.23.521780

bioRxiv · 10.1101/2022.12.23.521780

MYSM1 co-activates ERα action via histone and non-histone deubiquitination to confer antiestrogen resistance in breast cancer

Zhao, Y.·Luan, R.·Sun, G.·Zhou, B.·Wang, M.·Bai, Y.·Wang, C.·Wang, S.·Zeng, K.·Feng, J.·He, M.·Lin, L.·Wei, Y.·Zhang, Q.

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Abstract

Endocrine resistance is a crucial challenge in estrogen receptor alpha (ER)-positive breast cancer (BCa) therapy. Aberrant alteration in modulation of E2/ER signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Thus, identification the efficient ER cofactor remains necessary for finding a potential therapeutic target for endocrine resistance. Herein, we have demonstrated that Myb like, SWIRM and MPN domains 1 (MYSM1) as a histone deubiquitinase is a novel ER co-activator with established Drosophila experimental model. Our results showed that MYSM1 participated in up-regulation of ER action via histone and non-histone deubiquitination. We provided the evidence to show that MYSM1 was involved in maintenance of ER stability via ER deubiquitination. Furthermore, silencing MYSM1 induced enhancement of histone H2A ubiquitination as well as reduction of histone H3K4me3 and H3Ac levels at cis regulatory elements on promoter of ER-regulated gene. In addition, MYSM1 depletion attenuated cell proliferation/growth in BCa-derived cell lines and xenograft models. Knockdown of MYSM1 increased the sensitivity of antiestrogen agents in BCa cells. MYSM1 was highly expressed in clinical BCa samples, especially in aromatase inhibitor (AI) non-responsive tissues. 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.

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Zhao, Y., Luan, R., Sun, G., Zhou, B., Wang, M., Bai, Y., Wang, C., Wang, S., Zeng, K., Feng, J., He, M., Lin, L., Wei, Y., Zhang, Q.. 2022-12-24. MYSM1 co-activates ERα action via histone and non-histone deubiquitination to confer antiestrogen resistance in breast cancer. https://doi.org/10.1101/2022.12.23.521780

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