title: SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling.
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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Duan
authors.affiliation: Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.affiliation: Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.affiliation: Department of Physiology, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan. rhchen@gate.sinica.edu.tw.
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D000071156:Promyelocytic Leukemia Protein; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009687:Nuclear Proteins; D019696:Peptidylprolyl Isomerase; D010744:Phosphoric Monoester Hydrolases; D000071156:Promyelocytic Leukemia Protein; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C072087:sterol carrier proteins; C070576:PML protein, human; C546842:MTOR protein, human; C000606846:PIN1 protein, human