SCPs suppress renal cell carcinoma by regulating PML and mTOR/HIF pathway
Date Issued
2014
Date
2014
Author(s)
Lin, Yu-Ching
Abstract
The promyelocytic leukemia (PML) protein elicits pleiotropic tumor suppressive functions and is aberrantly degraded in multiple types of human cancers through incompletely understood mechanisms. Here, we show that the small C-terminal domain phosphatase 1/2/3 (SCP1/2/3) dephosphorylate PML at Ser518, thereby blocking PML ubiquitination and degradation mediated by peptidylprolyl cis/trans isomerase Pin1 and KLHL20-based ubiquitin ligase. Clinically, SCP1 and SCP3 are downregulated in clear cell renal cell carcinoma (ccRCC) and these downregulations correlate with PMLSer518 phosphorylation, PML downregulation, and high-grade tumor. Restoration of SCP1-mediated PML stabilization not only inhibits multiple malignant features of ccRCC, such as proliferation, migration, invasion, tumor growth in vivo, and angiogenesis, but also suppresses the mTOR/HIF pathway. Furthermore, blockage of PML degradation in ccRCC by SCP1 overexpression or Pin1 inhibition enhances the tumor suppressive effects of mTOR inhibitor temsirolimus. Our study identifies a PML degradation pathway in ccRCC through SCP downregulation, reveals the contribution of this pathway to ccRCC progression, and suggests a rationale for combinatory therapy that targets PML degradation and mTOR for ccRCC.
Subjects
SCP
dephosphorylation
clear cell renal cell carcinoma
SDGs
Type
thesis
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