The deubiquitinating enzyme USP15 stabilizes ERα and promotes breast cancer progression |
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Authors: | Xiaohong Xia Chuyi Huang Yuning Liao Yuan Liu Jinchan He Zhenlong Shao Tumei Hu Cuifu Yu Lili Jiang Jinbao Liu Hongbiao Huang |
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Institution: | 1.Affiliated Cancer Hospital & institute of Guangzhou Medical University, Guangzhou, 510095 China ;2.Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436 China |
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Abstract: | Breast cancer has the highest incidence and mortality in women worldwide. There are 70% of breast cancers considered as estrogen receptor α (ERα) positive. Therefore, the ERα-targeted therapy has become one of the most effective solution for patients with breast cancer. Whereas a better understanding of ERα regulation is critical to shape evolutional treatments for breast cancer. By exploring the regulatory mechanisms of ERα at levels of post-translational modifications, we identified the deubiquitinase USP15 as a novel protector for preventing ERα degradation and a critical driver for breast cancer progression. Specifically, we demonstrated that USP15 promoted the proliferation of ERα+, but not ERα- breast cancer, in vivo and in vitro. Meanwhile, USP15 knockdown notably enhanced the antitumor activities of tamoxifen on breast cancer cells. Importantly, USP15 knockdown induced the downregulation of ERα protein via promoting its K48-linked ubiquitination, which is required for proliferative inhibition of breast cancer cells. These findings not only provide a novel treatment for overcoming resistance to endocrine therapy, but also represent a therapeutic strategy on ERα degradation by targeting USP15-ERα axis.Subject terms: Breast cancer, Translational research |
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