G6PD promotes renal cell carcinoma proliferation through positive feedback regulation of p-STAT3.

Yingmin Kuang,Lijuan Yang,Yanling Wang,Xiaojia Yi,Qiaoqiao Han,Lu Jiang,Zihan Yi,Qiao Zhang,Honggang Bai,Zhe Yang,Yuechun Zhu,Xin Song

doi:10.18632/oncotarget.22566

Abstract

Ectopic Glucose 6-phosphate dehydrogenase (G6PD) expression plays important role in tumor cell metabolic reprogramming and results in poor prognosis of multiple malignancies. Our previous study indicated that G6PD is overexpressed in clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC. However, its role in RCC is still unclear. Here, we demonstrate that G6PD is not only up-regulated in all types of RCC specimens but also displays higher activities in RCC cell lines. G6PD overexpression promoted RCC cell proliferation, altered cell cycle distribution, and enhanced xenografted RCC development. G6PD up-regulated ROS generation by facilitating NADPH-dependent NOX4 activation, which led to increased expression of p-STAT3 and CyclinD1. Enhanced ROS generation rescued the p-STAT3 and CyclinD1 expression reduction in G6PD-knockdown cells, while ROS scavengers reversed the up-regulated p-STAT3 and CyclinD1 expression in G6PD-overexpressing cells. Furthermore, p-STAT3 activated G6PD gene expression via binding to the G6PD promoter, demonstrating that p-STAT3 forms a positive feedback regulatory loop for G6PD overexpression. G6PD expression was up or down-regulated in response to the impact of p-STAT3 activators or inhibitors. Therefore, G6PD may be an effective RCC therapeutic target.

Highlights

Glucose 6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), plays critical roles for nucleotide precursors generation and redox homeostasis maintenance [1]
We previously reported the aberrant expression of G6PD in clear cell renal cell carcinoma (ccRCC) [4]
We further explore the association between G6PD and renal cell carcinoma (RCC) through data mining of the public Gene Expression Omnibus (GEO) of 72 ccRCC and the adjacent non-tumor tissues (GSE53757)

Summary

Introduction

Glucose 6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), plays critical roles for nucleotide precursors generation and redox homeostasis maintenance [1]. Increasing evidences show that high expression of G6PD predicts poor overall survival of patients with numbers of cancers, indicating that G6PD may play important roles in tumorigenesis [1, 2]. Our recent studies demonstrate that G6PD is significantly higher expressed in advanced status of clear cell renal cell carcinoma (ccRCC) and closely correlates to the tumor extent, lymph node metastasis, Fuhrman grade, TNM stage and poor overall survival of ccRCC [4]. CcRCC is the most common subtypes of RCC and constitutes approximately 80~90% of RCCs. the expression pattern of G6PD in all the RCC cases is poorly reported, and the roles and underlying mechanisms of G6PD in RCC development, to date, remain largely unknown [4].

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