VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1\u03b1/HO-1 pathway

Ying Tong,Lin Guo,Yanchun Wang,Yiwen Yu,Hui Zheng,Keyu Zhu,Jinyan Kai,Renquan Lu,Xiaolin Guan,Suhong Xie,Yixuan Liu,Shuo Wang

doi:10.1038/s41419-021-03901-7

Abstract

Clear cell renal cell carcinomas (ccRCC) reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine. Recently, sirtuin 4 (SIRT4), a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment. However, the role of SIRT4 in ccRCC remains poorly understood. Here, we illustrated that the expression of SIRT4 is markedly reduced in cancerous tissues, and closely associated with malignancy stage, grade, and prognosis. In ccRCC cells, SIRT4 exerted its proapoptotic activity through enhancing intracellular reactive oxygen species (ROS). Heme oxygenase-1 (HO-1) is part of an endogenous defense system against oxidative stress. Nevertheless, overexpression of SIRT4 hindered the upregulation of HO-1 in von Hippel–Lindau (VHL)-proficient cells and repressed its expression in VHL-deficient cells. This discrepancy indicated that competent VHL withstands the inhibitory role of SIRT4 on HIF-1α/HO-1. Functionally, overexpression of HO-1 counteracted the promotional effects of SIRT4 on ROS accumulation and apoptosis. Mechanistically, SIRT4 modulates ROS and HO-1 expression via accommodating p38-MAPK phosphorylation. By contrast, downregulation of p38-MAPK by SB203580 decreased intracellular ROS level and enhanced the expression of HO-1. Collectively, this work revealed a potential role for SIRT4 in the stimulation of ROS and the modulation of apoptosis. SIRT4/HO-1 may act as a potential therapeutic target, especially in VHL-deficient ccRCCs.

Highlights

Clear cell renal cell carcinoma, ranking as the most common subtype, accounts for ~70–75% of renal cell carcinomas (RCCs) [1]
These findings demonstrate that Clear cell renal cell carcinoma (ccRCC) cells with defective von Hippel–Lindau (VHL) are more sensitive to glutamine deprivation or inhibition
This study demonstrated that sirtuin 4 (SIRT4) improved intracellular reactive oxygen species (ROS) and apoptosis in ccRCC cells through p38-MAPK phosphorylation

Summary

INTRODUCTION

Clear cell renal cell carcinoma (ccRCC), ranking as the most common subtype, accounts for ~70–75% of renal cell carcinomas (RCCs) [1]. Genes or proteins whose expressions are associated with lower tumor fitness and, better cancer patient survival in the context of VHL inactivation would theoretically be ideal targets for treating ccRCC. Glutamine is critical for many fundamental functions in cancer cells, such as generating antioxidants to remove reactive oxygen species (ROS), maintaining mitochondrial metabolism, and activating cell signaling [7]. Oxygenase-1 (HO-1) is a cytoprotective molecule with antioxidant, anti-inflammatory, and antiapoptotic properties It promotes Intracellular ROS level measurement resistance in various stress-related conditions. Western blot experiments were performed after the between SIRT4 expression and ROS roles in ccRCC cell lines. A greater insight into mechanisms on the sensitivity of ccRCC cells 10% polyacrylamide gel electrophoresis and transferred to PVDF to SIRT4- restricted glutamine metabolism, setting the membranes (Invitrogen, ISEQ00010).

MATERIAL AND METHODS

DISCUSSION

ETHICS STATEMENT