SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling

Yu Ching Lin, Li Ting Lu, Hsin Yi Chen, Xueyan Duan, Xia Lin, Xin Hua Feng, Ming Jer Tang, Ruey Hwa Chen

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The tumor-suppressor protein promyelocytic leukemia (PML) is aberrantly degraded in multiple types of human cancers through mechanisms that are incompletely understood. Here, we show that the phosphatase SCP1 and its isoforms SCP2/3 dephosphorylate PML at S518, thereby blocking PML ubiquitination and degradation mediated by the prolyl isomerase Pin1 and the ubiquitin ligase KLHL20. Clinically, SCP1 and SCP3 are downregulated in clear cell renal cell carcinoma (ccRCC) and these events correlated with PMLS518 phosphorylation, PML turnover, and high-grade tumors. Restoring SCP1-mediated PML stabilization not only inhibited malignant features of ccRCC, including proliferation, migration, invasion, tumor growth, and tumor angiogenesis, but also suppressed the mTOR-HIF pathway. Furthermore, blocking PML degradation in ccRCC by SCP1 overexpression or Pin1 inhibition enhanced the tumor-suppressive effects of the mTOR inhibitor temsirolimus. Taken together, our results define a novel pathway of PML degradation in ccRCC that involves SCP downregulation, revealing contributions of this pathway to ccRCC progression and offering a mechanistic rationale for combination therapies that jointly target PML degradation and mTOR inhibition for ccRCC treatment.

Original languageEnglish
Pages (from-to)6935-6946
Number of pages12
JournalCancer Research
Volume74
Issue number23
DOIs
Publication statusPublished - Dec 1 2014

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Renal Cell Carcinoma
Phosphoric Monoester Hydrolases
Leukemia
Neoplasms
Down-Regulation
Peptidylprolyl Isomerase
Tumor Suppressor Proteins
Ubiquitination
Ligases
Ubiquitin
Protein Isoforms
Phosphorylation
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling. / Lin, Yu Ching; Lu, Li Ting; Chen, Hsin Yi; Duan, Xueyan; Lin, Xia; Feng, Xin Hua; Tang, Ming Jer; Chen, Ruey Hwa.

In: Cancer Research, Vol. 74, No. 23, 01.12.2014, p. 6935-6946.

Research output: Contribution to journalArticle

Lin, Yu Ching ; Lu, Li Ting ; Chen, Hsin Yi ; Duan, Xueyan ; Lin, Xia ; Feng, Xin Hua ; Tang, Ming Jer ; Chen, Ruey Hwa. / SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling. In: Cancer Research. 2014 ; Vol. 74, No. 23. pp. 6935-6946.
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