Journal
CANCER SCIENCE
Volume 112, Issue 10, Pages 4100-4111Publisher
WILEY
DOI: 10.1111/cas.15096
Keywords
acquired sorafenib resistance; clear cell renal cell carcinoma; HIF-2 alpha; pVHL; SHARPIN
Categories
Funding
- National Natural Science Foundation of China [81602227]
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SHARPIN upregulation in ccRCC patients leads to poor prognosis and is positively associated with HIF-2α; SHARPIN promotes the ubiquitination and degradation of pVHL to sustain HIF-2α activation.
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 arid the results suggested the positive association between SHARPIN and hypoxia-induced factor-2 alpha (HIF-2 alpha). Von Hippel-Lindau protein (pVHL) is a tumor suppressor that contributes to degrading HIF 2 alpha. Mechanically, SHARPIN promoted the ubiquitination and proteasomal degradation of pVHL, resulting in the sustained activation of HIF-2 alpha. The alpha and beta 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.
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