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  3. The GPER1/SPOP axis mediates ubiquitination-dependent degradation of ERα to inhibit the growth of breast cancer induced by oestrogen

The GPER1/SPOP axis mediates ubiquitination-dependent degradation of ERα to inhibit the growth of breast cancer induced by oestrogen

  • Cancer Lett. 2021 Feb 1;498:54-69. doi: 10.1016/j.canlet.2020.10.019.
Nan Zhang 1,  Peng Sun 2,  Yuanyuan Xu 1,  Haiyan Li 3,  Huatao Liu 1,  Ling Wang 1,  Yue Cao 1,  Kewen Zhou 4,  TinghuaiWang 5
Affiliations

Affiliations

  • 1 Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University,. Zhongshan Road 2, Guangzhou 510080, PR China.
  • 2 Department of Pathology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Dongfeng East Road, Guangzhou 510080, PR China.
  • 3 Department of Breast Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, PR China.
  • 4 Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University,. Zhongshan Road 2, Guangzhou 510080, PR China. Electronic address: zhoukw6@mail.sysu.edu.cn.
  • 5 Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University,. Zhongshan Road 2, Guangzhou 510080, PR China. Electronic address: wangth@mail.sysu.edu.cn.
PMID: 33069770 DOI: 10.1016/j.canlet.2020.10.019
Abstract

G protein-coupled oestrogen receptor 1 (GPER1), predicted to be a novel oestrogen receptor, has been linked to the development and progression of breast Cancer. However, the molecular mechanisms underlying its functions remain elusive. Here, we show that the protein levels of GPER1 are negatively associated with those of ERα and that higher expression of GPER1 correlated with a better clinical outcome in oestrogen receptor-positive (ER+) breast Cancer patients. Activation of GPER1 decreases ERα protein levels, which subsequently suppresses ERα-mediated transcription and target gene expression but does not affect its mRNA expression in ER + breast Cancer cells. A mechanistic study revealed that GPER1 mediates ubiquitin (Ub)-proteasome-dependent degradation of ERα via upregulation of the Cullin3-based E3 ubiquitin Ligase adaptor protein speckle-type POZ protein (SPOP), and depletion of SPOP abrogates GPER1-induced ERα ubiquitination and degradation. Functionally, GPER1 activation inhibits 17β-oestradiol (E2)-induced ER + breast Cancer cell proliferation, migration, and invasion in vitro and tumour growth in vivo. Our findings reveal a novel mechanism by which GPER1 negatively modulates the ERα signalling pathway via promoting its ubiquitin-proteasome-dependent degradation, which may contribute to its inhibition of breast Cancer progression.

Keywords

GPCR; Hormone receptor; Nuclear receptor; Protein interaction; Ubiquitin-proteasome pathway.

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