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

// Qiao Zhang 1, * , Zhe Yang 2, * , Qiaoqiao Han 1, * , Honggang Bai 1 , Yanling Wang 1 , Xiaojia Yi 3 , Zihan Yi 1 , Lijuan Yang 1 , Lu Jiang 1 , Xin Song 4 , Yingmin Kuang 5 and Yuechun Zhu 1 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Chenggong District, Kunming 650500, Yunnan Province, China 2 Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming 650032, Yunnan Province, China 3 Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming 650101, Yunnan Province, China 4 Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University, Xishan District, Kunming 650118, Yunnan Province, China 5 Department of Organ Transplantation, The First Affiliated Hospital of Kunming Medical University, Wuhua District, Kunming 650032, Yunnan Province, China * These authors have contributed equally to this work Correspondence to: Yuechun Zhu, email: zhuyuechun20091119@163.com Yingmin Kuang, email: yingmin1512@aliyun.com Keywords: G6PD; renal cell carcinoma; proliferation; p-STAT3; positive feedback regulation Received: August 09, 2017     Accepted: September 22, 2017     Published: November 20, 2017 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.