SPOP Promotes Tumorigenesis by Acting as a Key Regulatory Hub in Kidney Cancer
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels une surexpression du gène SPOP, qui code une ubiquitine ligase, favorise le développement d'un carcinome rénal à cellules claires
Hypoxic stress and hypoxia-inducible factors (HIFs) play important roles in a wide range of tumors. We demonstrate that SPOP, which encodes an E3 ubiquitin ligase component, is a direct transcriptional target of HIFs in clear cell renal cell carcinoma (ccRCC). Furthermore, hypoxia results in cytoplasmic accumulation of SPOP, which is sufficient to induce tumorigenesis. This tumorigenic activity occurs through the ubiquitination and degradation of multiple regulators of cellular proliferation and apoptosis, including the tumor suppressor PTEN, ERK phosphatases, the proapoptotic molecule Daxx, and the Hedgehog pathway transcription factor Gli2. Knockdown of SPOP specifically kills ccRCC cells, indicating that it may be a promising therapeutic target. Collectively, our results indicate that SPOP serves as a regulatory hub to promote ccRCC tumorigenesis. "Transcriptional factor HIF can regulate the expression of SPOP in ccRCC "Hypoxia drives SPOP accumulation in ccRCC cell cytoplasm which promotes tumorigenesis "SPOP mediates the ubiquitination and degradation of PTEN and DUSP7 "SPOP targets PTEN, DUSP7, DAXX, and Gli2, are downregulated in all primary ccRCC Li et al. demonstrate that hypoxia drives the cytoplasmic accumulation of SPOP, an E3 ubiquitin ligase component, in clear cell renal cell carcinoma (ccRCC). Cytoplasmic SPOP promotes tumorigenesis by targeting tumor suppressors, including PTEN, for degradation and could be a promising therapeutic target in ccRCC.