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

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

doi:10.18632/oncotarget.12606

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.

Highlights

Renal cell carcinoma (RCC) is the ninth most common cancer worldwide, with about 337,860 new cases diagnosed in 2012 [1]
We found that the levels of lactate and pyruvate were significantly higher in tumor from the SENP1 high-expression group than in the SENP1 low-expression group (P < 0.01, Table 2), suggesting a potential positive correlation between Sentrin/SUMO-specific proteases (SENPs) expression level and glycolysis in clear cell renal cell carcinoma (ccRCC) tumors
We and others have previously demonstrated that clear cell renal-cell carcinoma, the most common RCC subtype, features different metabolite profiles compared to adjacent normal kidney tissues, including elevated levels of lactate, glutamate, pyruvate, glutamine, and creatine, but decreased levels of acetate, malate, and amino acids such as valine, alanine, and aspartate, indicating enhanced glycolysis and diminished tricarboxylic acid (TCA) cycle activity in ccRCC [21,22,23,24]

Summary

Introduction

Renal cell carcinoma (RCC) is the ninth most common cancer worldwide, with about 337,860 new cases diagnosed in 2012 [1]. Further studies have revealed that ccRCC is a heterogeneous cancer with disparate genetic and molecular alterations beyond VHL mutation, such as mutations in genes encoding chromatin remodeling proteins, like polybromo 1(PBRM1) [4] and SET domain containing 2 (SETD2) [5], both associated with high tumor stage and poor prognosis. These studies suggest that additional genetic/epigenetic events should be considered to explain the diverse oncogenic and proliferative behavior of ccRCC

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Results

Conclusion