title: SENP1 promotes proliferation of clear cell renal cell carcinoma through activation of glycolysis.
abstract: Metabolic shift toward aerobic glycolysis is a fundamental element contributing to the development and progression of clear cell renal cell carcinoma (ccRCC). We and others previously observed enhanced glycolysis and diminished tricarboxylic acid (TCA) cycle activity in ccRCC tissue. Here, by integrated gene expression and metabolomic analyses of 36 matched pairs of tumor and adjacent normal tissues, we showed that expression of Sentrin/SUMO-specific protease 1 (SENP1) is positively associated with glycolysis levels in ccRCC. Moreover, SENP1 knockdown in RCC4/VHL cells downregulated expression of key glycolytic enzymes under normoxic and hypoxic conditions and inhibited cell proliferation under hypoxic conditions, possibly due to ineffective deSUMOylation and stablization of Hif-1α related to the SENP-1 deficiency. Finally, SENP1 expression correlated positively with tumor pathological grade and was an indicator of poor overall survival and advanced tumor progression in ccRCC. Altered VHL gene function is found in 60-90% ccRCC cases of ccRCC, but therapies targeting VHL-related signaling pathways have been ineffective, spurring exploration of alternative pathological signaling events. Our results provide a possible mechanistic explanation for the role of SENP1 in the initiation and development of ccRCC with normal VHL activity, and identifies SENP1 as a potential treatment target for the disease.
authors.affiliation: Department of Urology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Baijun
authors.initials: B
authors.lastname: Dong
authors.affiliation: Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, Ningxia Medical University, Yinchuan, Ningxia, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xunlei
authors.initials: X
authors.lastname: Kang
authors.affiliation: School of Pharmacy, Wenzhou Medical College, Wenzhou, China.
authors.forename: Hongchang
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Urology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, USA.|Current address: North Shore LIJ Health System, New York, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, USA.|The Graduate School of Biomedical Science, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Mingjian J
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Urology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xue
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jinke
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Urology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Huang
mesh_terms: D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D058207:Sumoylation; D013997:Time Factors; D014162:Transfection; D000072258:Tumor Hypoxia; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C497446:VHL protein, human
keywords: HIF-1α; SENP1; clear cell renal cell carcinoma; glycolysis