SHARPIN stabilizes estrogen receptor ? and promotes breast cancer cell proliferation.

ABSTRACT: Estrogen receptor ? is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. In our study, we identified the novel E3 ubiquitin ligase SHARPIN function to facilitate ER? signaling. SHARPIN is highly expressed in human breast cancer and correlates with ER? protein level by immunohistochemistry. SHARPIN expression level correlates with poor prognosis in ER? positive breast cancer patients. SHARPIN depletion based RNA-sequence data shows that ER? signaling is a potential SHARPIN target. SHARPIN depletion significantly decreases ER? protein level, ER? target genes expression and estrogen response element activity in breast cancer cells, while SHARPIN overexpression could reverse these effects. SHARPIN depletion significantly decreases estrogen stimulated cell proliferation in breast cancer cells, which effect could be further rescued by ER? overexpression. Further mechanistic study reveals that SHARPIN mainly localizes in the cytosol and interacts with ER? both in the cytosol and the nuclear. SHARPIN regulates ER? signaling through protein stability, not through gene expression. SHARPIN stabilizes ER? protein via prohibiting ER? protein poly-ubiquitination. Further study shows that SHARPIN could facilitate the mono-ubiquitinaiton of ER? at K302/303 sites and facilitate ERE luciferase activity. Together, our findings propose a novel ER? modulation mechanism in supporting breast cancer cell growth, in which SHARPIN could be one suitable target for development of novel therapy for ER? positive breast cancer.

SUBMITTER: Zhuang T 

PROVIDER: S-EPMC5652769 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature