Abstract
AbstractAlthough E3 ligase Speckle type BTB/POZ protein (SPOP) promotes tumorigenesis by acting as a key regulatory hub in clear cell renal cell carcinoma (ccRCC), the detailed molecular mechanism remains unclear. Here, we demonstrate that a well-known tumor suppressor, Suppressor of Fused (SUFU), is downregulated by SPOP. Interestingly, this downregulation depends on cullin-3(Cul3)-SPOP E3 ligase, but SUFU is not a direct substrate of SPOP. Phosphatase and tensin homolog (PTEN), a ubiquitinated substrate of SPOP, is involved in SPOP-mediated SUFU reduction. Importantly, inhibition of SUFU leads to elevated SHH and WNT signaling, consequently rescuing the reduced proliferation, migration, and invasion abilities of ccRCC cells caused by SPOP-knockdown. Moreover, combinatorial treatment with SHH and WNT inhibitors shows more effective for suppressing ccRCC cell proliferation and aggressiveness. These findings demonstrate that a novel SPOP–PTEN–SUFU axis promotes ccRCC carcinogenesis by activating SHH and WNT pathway, providing a new treatment strategy for ccRCC.
Funder
National Science Foundation of China | Young Scientists Fund
Natural Science Foundation of Jiangsu Province
Henan University of Science and Technology
Nanjing Medical University
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Cited by
2 articles.
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