Functional deficiency of succinate dehydrogenase promotes tumorigenesis and development of clear cell renal cell carcinoma through weakening of ferroptosis

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas, with high mortality and poor prognoses worldwide. Succinate dehydrogenase (SDH) consists of four nuclear-encoded subunits and it is the only complex involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Previous studies have shown decreased SDH activity in ccRCC. However, the role and underlying molecular mechanisms of SDH in ccRCC initiation and development remain unclear. In the present study, pan-cancer analysis of SDH gene expression was analyzed and the relationship between SDH gene expression and clinicopathological parameters was assessed using different databases. cBioPortal, UACLAN, and Tumor Immune Estimation Resource (TIMER) were subsequently utilized to analyze genetic alterations, methylation, and immune cell infiltration of SDH genes in ccRCC patients. We found SDHs were significantly downregulated in ccRCC tissues and correlated with ccRCC progression. Increased methylation and high SDH promoter mutation rates may be the cause of reduced expression of SDHs in ccRCC. Moreover, the interaction network showed that SDH genes were correlated with ferroptosis-related genes. We further demonstrated that SDH inhibition dampened oxidative phosphorylation, reduced ferroptotic events, and restored ferroptotic cell death, characterized by eliminated mitochondrial ROS levels, decreased cellular ROS and diminished peroxide accumulation. Collectively, this study provides new insights into the regulatory role of SDH in the carcinogenesis and progression of ccRCC, introducing a potential target for advanced antitumor therapy through ferroptosis.

Identification of mitochondrial respiratory chain signature for predicting prognosis and immunotherapy response in stomach adenocarcinoma

“…Our previous work has found that achieving ferroptosis via ferroptosis-inducing drugs is effective in many cancers [ 36 – 39 ]. Moreover, our recent studies demonstrated that inhibition of mitochondrial ETC (electron transport chain) attenuates ferroptotic cell death [ 40 ]. In this study, heatmaps of expression differences in ferroptosis genes among MRCCGs patterns were presented (Fig S4 ).…”

PTK6: An emerging biomarker for prognosis and immunotherapeutic response in clear cell renal carcinoma (KIRC)

“…Recently, a study demonstrated the mechanism underlying the regulatory role of SDH in carcinogenesis and progression of KIRC is that inhibition of SDH suppresses oxidative phosphorylation, reduces ferroptosis events, and restores ferroptosis, which is characterized by reduced mitochondrial ROS levels, reduced cellular ROS, and reduced peroxide accumulation. Consequently, PTK6 may be a biomarker with therapeutic and preventive potential for KIRC [ 74 ]. In the future, we will focus on doing more experiments to verify our speculations.…”

Novel Insight into Ferroptosis in Kidney Diseases

“…miRNA-4735-3p targeted SLC40A1 to facilitate ferroptosis in ccRCC [89], and CX3CL1 enhanced cell susceptibility to ferroptosis and was related to the tumor microenvironment [90]. Ferroptosis was weakened by succinate dehydrogenase's functional deficit, which encouraged tumorigenesis and the growth of ccRCC [91]. The high sensitivity of the murine A/J strain to iron-induced renal carcinogenesis was determined by ferroptosis resistance [92].…”