A HIF1\u03b1-GPD1 feedforward loop inhibits the progression of renal clear cell carcinoma via mitochondrial function and lipid metabolism

Ren Liu,Chin-Lee Wu,Hui Zhang,Chi Tin Hon,Qingling Xie,Zhaodong Han,Jianheng Ye,Zhihao Zou,Jianming Lu,Yangjia Zhuo,Yuxiang Liang,Weide Zhong,Yuanfa Feng,Yong Luo,Yingke Liang,Xuejin Zhu,Yulin Deng,Zhiduan Cai

doi:10.1186/s13046-021-01996-6

Abstract

BackgroundHypoxia signaling, especially the hypoxia inducible factor (HIF) pathway, is a major player in clear cell renal cell carcinoma (ccRCC), which is characterized by disorders in lipid and glycogen metabolism. However, the interaction between hypoxia and lipid metabolism in ccRCC progression is still poorly understood.MethodsWe used bioinformatic analysis and discovered that glycerol-3-phosphate dehydrogenase 1 (GPD1) may play a key role in hypoxia and lipid metabolism pathways in ccRCC. Tissue microarray, IHC staining, and survival analysis were performed to evaluate clinical function. In vitro and in vivo assays showed the biological effects of GPD1 in ccRCC progression.ResultsWe found that the expression of GPD1 was downregulated in ccRCC tissues, and overexpression of GPD1 inhibited the progression of ccRCC both in vivo and in vitro. Furthermore, we demonstrated that hypoxia inducible factor-1α (HIF1α) directly regulates GPD1 at the transcriptional level, which leads to the inhibition of mitochondrial function and lipid metabolism. Additionally, GPD1 was shown to inhibit prolyl hydroxylase 3 (PHD3), which blocks prolyl-hydroxylation of HIF1α and subsequent proteasomal degradation, and thus reinforces the inhibition of mitochondrial function and phosphorylation of AMPK via suppressing glycerol-3-phosphate dehydrogenase 2 (GPD2).ConclusionsThis study not only demonstrated that HIF1α-GPD1 forms a positive feedforward loop inhibiting mitochondrial function and lipid metabolism in ccRCC, but also discovered a new mechanism for the molecular basis of HIF1α to inhibit tumor activity, thus providing novel insights into hypoxia-lipid-mediated ccRCC therapy.

Highlights

Hypoxia signaling, especially the hypoxia inducible factor (HIF) pathway, is a major player in clear cell renal cell carcinoma, which is characterized by disorders in lipid and glycogen metabolism
This study demonstrated that hypoxia inducible factor-1α (HIF1α)-glycerol-3-phosphate dehydrogenase 1 (GPD1) forms a positive feedforward loop inhibiting mitochondrial function and lipid metabolism in clear cell renal cell carcinoma (ccRCC), and discovered a new mechanism for the molecular basis of HIF1α to inhibit tumor activity, providing novel insights into hypoxia-lipid-mediated ccRCC therapy
GPD1 serves an important role in hypoxia and lipid metabolism pathways in ccRCC The discovery cohort contained 530 ccRCC patients from the The Cancer Genome Atlas (TCGA) database, including the corresponding RNA-seq results and clinical information

Summary

Introduction

Especially the hypoxia inducible factor (HIF) pathway, is a major player in clear cell renal cell carcinoma (ccRCC), which is characterized by disorders in lipid and glycogen metabolism. Renal cancer is a common urologic cancer, and the pathological classification is diverse It consists mainly of renal clear cell carcinoma, most of which occurs in renal tubular epithelial cells [1]. In contrast to many tumor types, HIF1α and HIF2α have opposite roles in ccRCC biology, where HIF1α acts as a tumor suppressor and HIF2α acts as an oncogene [4]. Only one study by Florinda et al has shown that HIF1α functions as an inhibitor of aspartate biogenesis by repressing glutamine oxidation and reductive carboxylation pathways via negatively regulating two key players, cytosolic glutamic-oxaloacetic transaminase-1 (GOT1) and mitochondrial GOT2 [6]

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Results

Conclusion