SHARPIN stabilizes estrogen receptor a and promotes breast cancer cell proliferation

Estrogen receptor a 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 alpha signaling. SHARPIN is highly expressed in human breast cancer and correlates with ER alpha protein level by immunohistochemistry. SHARPIN expression level correlates with poor prognosis in ER alpha positive breast cancer patients. SHARPIN depletion based RNA-sequence data shows that ER alpha signaling is a potential SHARPIN target. SHARPIN depletion significantly decreases ER alpha protein level, ER alpha 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 alpha overexpression. Further mechanistic study reveals that SHARPIN mainly localizes in the cytosol and interacts with ER alpha both in the cytosol and the nuclear. SHARPIN regulates ER alpha signaling through protein stability, not through gene expression. SHARPIN stabilizes ER alpha protein via prohibiting ER alpha protein poly-ubiquitination. Further study shows that SHARPIN could facilitate the mono-ubiquitinaiton of ER alpha at K302/303 sites and facilitate ERE luciferase activity. Together, our findings propose a novel ER alpha modulation mechanism in supporting breast cancer cell growth, in which SHARPIN could be one suitable target for development of novel therapy for ER alpha positive breast cancer.