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

doi:10.1158/0008-5472.CAN-14-1330

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

Cancer Res. 2014 Dec 1;74(23):6935-46. doi: 10.1158/0008-5472.CAN-14-1330. Epub 2014 Oct 7.

Authors

Yu-Ching Lin¹, Li-Ting Lu¹, Hsin-Yi Chen², Xueyan Duan³, Xia Lin⁴, Xin-Hua Feng³, Ming-Jer Tang⁵, Ruey-Hwa Chen⁶

Affiliations

¹ Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
² Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
³ Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
⁴ Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
⁵ Department of Physiology, National Cheng Kung University Medical College, Tainan, Taiwan.
⁶ Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan. rhchen@gate.sinica.edu.tw.

PMID: 25293974
DOI: 10.1158/0008-5472.CAN-14-1330

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Basic Helix-Loop-Helix Transcription Factors / genetics*
Basic Helix-Loop-Helix Transcription Factors / metabolism
Carcinoma, Renal Cell / genetics*
Carcinoma, Renal Cell / metabolism
Carrier Proteins / genetics*
Cell Line
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
Down-Regulation / genetics
Gene Expression Regulation, Neoplastic / genetics
HEK293 Cells
HeLa Cells
Humans
Kidney Neoplasms / genetics*
Kidney Neoplasms / metabolism
NIMA-Interacting Peptidylprolyl Isomerase
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Peptidylprolyl Isomerase / genetics
Peptidylprolyl Isomerase / metabolism
Phosphoric Monoester Hydrolases / genetics
Phosphoric Monoester Hydrolases / metabolism
Phosphorylation / genetics
Promyelocytic Leukemia Protein
Signal Transduction / genetics
TOR Serine-Threonine Kinases / genetics*
TOR Serine-Threonine Kinases / metabolism
Transcription Factors / genetics*
Transcription Factors / metabolism
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism

Substances

Basic Helix-Loop-Helix Transcription Factors
Carrier Proteins
NIMA-Interacting Peptidylprolyl Isomerase
Nuclear Proteins
Promyelocytic Leukemia Protein
Transcription Factors
Tumor Suppressor Proteins
sterol carrier proteins
PML protein, human
MTOR protein, human
TOR Serine-Threonine Kinases
Phosphoric Monoester Hydrolases
PIN1 protein, human
Peptidylprolyl Isomerase