Oncotarget

Research Papers:

SENP1 promotes proliferation of clear cell renal cell carcinoma through activation of glycolysis

Baijun Dong, Yujing Gao, Xunlei Kang, Hongchang Gao, Jin Zhang, Hua Guo, Mingjian J You, Wei Xue, Jinke Cheng and Yiran Huang _

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Oncotarget. 2016; 7:80435-80449. https://doi.org/10.18632/oncotarget.12606

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Abstract

Baijun Dong1,*, Yujing Gao2,*, Xunlei Kang3,*, Hongchang Gao4,*, Jin Zhang1, Hua Guo5,7, Mingjian J You5,6, Wei Xue1, Jinke Cheng3, Yiran Huang1

1Department of Urology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China

2Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, Ningxia Medical University, Yinchuan, Ningxia, China

3Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

4School of Pharmacy, Wenzhou Medical College, Wenzhou, China

5Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, USA

6The Graduate School of Biomedical Science, University of Texas MD Anderson Cancer Center, Houston, USA

7Current address: North Shore LIJ Health System, New York, USA

*These authors contributed equally to this work

Correspondence to:

Yiran Huang, email: [email protected]

Jinke Cheng, email: [email protected]

Keywords: SENP1, glycolysis, HIF-1α, clear cell renal cell carcinoma

Received: May 29, 2016     Accepted: October 03, 2016     Published: October 12, 2016

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.


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