Open AccessSHARPIN regulates the development of clear cell renal cell carcinoma by promoting von Hippel‐Lindau protein ubiquitination and degradation
Author(s) -
Yin Rusha,
Liu Shuai
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15096
Subject(s) - clear cell renal cell carcinoma , ubiquitin , cancer research , gene knockdown , downregulation and upregulation , carcinogenesis , biology , cell culture , cell growth , hek 293 cells , protein degradation , cancer , microbiology and biotechnology , renal cell carcinoma , pathology , medicine , biochemistry , genetics , gene
SHANK‐associated RH domain interacting protein (SHARPIN) plays an important role in carcinogenesis, as well as inflammation and immunity. Our study explored the effects and underlying mechanisms of SHARPIN in clear cell renal cell carcinoma (ccRCC). By analyzing The Cancer Genome Atlas database, we found that upregulated SHARPIN in patients with ccRCC led to a poor prognosis. Semiquantitative immunohistochemical analysis of clinical samples was carried out and the results suggested the positive association between SHARPIN and hypoxia‐induced factor‐2α (HIF‐2α). Von Hippel‐Lindau protein (pVHL) is a tumor suppressor that contributes to degrading HIF‐2α. Mechanically, SHARPIN promoted the ubiquitination and proteasomal degradation of pVHL, resulting in the sustained activation of HIF‐2α. The α and β domains of pVHL and ubiquitin‐like domain of SHARPIN are required for the interaction. The knockdown of SHARPIN effectively inhibited acquired sorafenib resistance in ccRCC cell lines and tumor growth in xenograft models. In conclusion, our work reveals a novel posttranslational regulation of SHARPIN on pVHL, indicating that SHARPIN could be a potential target for ccRCC treatment.