SHARPIN regulates the development of clear cell renal cell carcinoma by promoting von Hippel‐Lindau protein ubiquitination and degradation

• Published in: Cancer science 2021-10, Vol.112 (10), p.4100-4111
• Main Authors: Yin, Rusha, Liu, Shuai
• Format: Article
• Language: English
• Subjects: acquired sorafenib resistance; Amino acids; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biotechnology; Carcinogenesis; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - etiology; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; clear cell renal cell carcinoma; Clear cell-type renal cell carcinoma; Cloning; Drug Resistance, Neoplasm - genetics; Female; Gene expression; Gene Silencing; Genomes; Heterografts; HIF‐2α; Humans; Hypoxia; Kaplan-Meier Estimate; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - etiology; Kidney Neoplasms - pathology; Kinases; Male; Medical prognosis; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Original; Patients; Prognosis; Proteasomes; Protein Kinase Inhibitors - pharmacology; Protein Processing, Post-Translational; Proteins; Proteolysis; pVHL; Random Allocation; RNA, Small Interfering; SHARPIN; Sorafenib - pharmacology; Tumor cell lines; Tumor suppressor genes; Ubiquitin; Ubiquitination; Ubiquitins - genetics; Ubiquitins - metabolism; Ubiquitins - physiology; Up-Regulation; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; Xenografts
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15096

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. SHARPIN promotes the ubiquitination and proteasomal degradation of von Hippel‐Lindau protein (pVHL) through the interaction between the ubiquitin‐like domain of SHARPIN and the α and β domains of pVHL, resulting in the sustained activation of hypoxia‐induced factor‐2α. The knockdown of SHARPIN effectively inhibited acquired sorafenib resistance in clear cell renal cell carcinoma cell lines and tumor growth in xenograft models.