Advanced

SHARPIN stabilizes estrogen receptor a and promotes breast cancer cell proliferation

Zhuang, Ting; Yu, Sifan; Zhang, Lichen; Yang, Huijie; Li, Xin; Hou, Yingxiang; Liu, Zhenhua; Shi, Yuanyuan; Wang, Weilong and Yu, Na, et al. (2017) In Oncotarget 8(44). p.77137-77151
Abstract

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 ERα signaling. SHARPIN is highly expressed in human breast cancer and correlates with ERα protein level by immunohistochemistry. SHARPIN expression level correlates with poor prognosis in ERα positive breast cancer patients. SHARPIN depletion based RNA-sequence data shows that ERα signaling is a potential SHARPIN target. SHARPIN depletion significantly decreases ERα protein level, ERα target genes expression and estrogen response element activity in breast cancer cells, while SHARPIN overexpression could reverse these effects.... (More)

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

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast cancer, ER alpha, Protein stability, SHARPIN, Ubiquitination
in
Oncotarget
volume
8
issue
44
pages
15 pages
publisher
Impact Journals, LLC
external identifiers
  • scopus:85030312332
ISSN
1949-2553
DOI
10.18632/oncotarget.20368
language
English
LU publication?
yes
id
0e4bcd15-3e0a-41c6-8797-3328912e57c5
date added to LUP
2017-11-07 15:50:25
date last changed
2018-01-07 12:25:15
@article{0e4bcd15-3e0a-41c6-8797-3328912e57c5,
  abstract     = {<p>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 ERα signaling. SHARPIN is highly expressed in human breast cancer and correlates with ERα protein level by immunohistochemistry. SHARPIN expression level correlates with poor prognosis in ERα positive breast cancer patients. SHARPIN depletion based RNA-sequence data shows that ERα signaling is a potential SHARPIN target. SHARPIN depletion significantly decreases ERα protein level, ERα 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 ERα overexpression. Further mechanistic study reveals that SHARPIN mainly localizes in the cytosol and interacts with ERα both in the cytosol and the nuclear. SHARPIN regulates ERα signaling through protein stability, not through gene expression. SHARPIN stabilizes ERα protein via prohibiting ERα protein poly-ubiquitination. Further study shows that SHARPIN could facilitate the mono-ubiquitinaiton of ERα at K302/303 sites and facilitate ERE luciferase activity. Together, our findings propose a novel ERα modulation mechanism in supporting breast cancer cell growth, in which SHARPIN could be one suitable target for development of novel therapy for ERα positive breast cancer.</p>},
  author       = {Zhuang, Ting and Yu, Sifan and Zhang, Lichen and Yang, Huijie and Li, Xin and Hou, Yingxiang and Liu, Zhenhua and Shi, Yuanyuan and Wang, Weilong and Yu, Na and Li, Anqi and Li, Xuefeng and Li, Xiumin and Niu, Gang and Xu, Juntao and Hasni, Muhammad Sharif and Mu, Kun and Wang, Hui and Zhu, Jian},
  issn         = {1949-2553},
  keyword      = {Breast cancer,ER alpha,Protein stability,SHARPIN,Ubiquitination},
  language     = {eng},
  number       = {44},
  pages        = {77137--77151},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {SHARPIN stabilizes estrogen receptor a and promotes breast cancer cell proliferation},
  url          = {http://dx.doi.org/10.18632/oncotarget.20368},
  volume       = {8},
  year         = {2017},
}