Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer

Abstract

Reduced succinate dehydrogenase (SDH) activity resulting in adverse succinate accumulation was previously considered relevant only in 0.05 to 0.5% of kidney cancers associated with germline SDH mutations. Here, we sought to examine a broader role for SDH loss in kidney cancer pathogenesis/progression. We report that underexpression of SDH subunits resulting in accumulation of oncogenic succinate is a common feature in clear cell renal cell carcinoma (ccRCC) (∼80% of all kidney cancers), with a marked adverse impact on survival in ccRCC patients (n = 516). We show that SDH down-regulation is a critical brake in the TCA cycle during ccRCC pathogenesis and progression. In exploring mechanisms of SDH down-regulation in ccRCC, we report that Von Hippel-Lindau loss-induced hypoxia-inducible factor–dependent up-regulation of miR-210 causes direct inhibition of the SDHD transcript. Moreover, shallow deletion of SDHB occurs in ∼20% of ccRCC. We then demonstrate that SDH loss-induced succinate accumulation contributes to adverse loss of 5-hydroxymethylcytosine, gain of 5-methylcytosine, and enhanced invasiveness in ccRCC via inhibition of ten-eleven translocation (TET)-2 activity. Intriguingly, binding affinity between the catalytic domain of recombinant TET-2 and succinate was found to be very low, suggesting that the mechanism of succinate-induced attenuation of TET-2 activity is likely via product inhibition rather than competitive inhibition. Finally, exogenous ascorbic acid, a TET-activating demethylating agent, led to reversal of the above oncogenic effects of succinate in ccRCC cells. Collectively, our study demonstrates that functional SDH deficiency is a common adverse feature of ccRCC and not just limited to the kidney cancers associated with germline SDH mutations.

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

“…SDH inhibition could restore ferroptotic cell death. A recent study showed that SDH dysfunction leads to the accumulation of succinate, resulting in a gain of 5-methylcytosine, and eventually enhancing the invasiveness of ccRCC by inhibiting ten-eleven translocation-2 activity [ 60 ]. As SDH is the only complex that takes part in both the TCA cycle and OXPHOS, succinate accumulation leads to the succination of Keap1, NRF2 stabilization, and the transcriptional activation of stress-response genes, thus promoting the antioxidant phenotype [ 61 ].…”

Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma

“…In addition, molecular patterns involving metabolic pathways correlated with worse survival in ccRCC, including downregulation of AMP-activated kinase (AMPK) complex and the Krebs cycle genes, upregulation of genes involved in the pentose phosphate pathway and fatty acid synthesis (15). Functional deficiency of succinate dehydrogenase (SDH), resulting in succinate accumulation, is a common feature in up to 80% of ccRCCs (16). Survival analyses of the TCGA-KIRC dataset confirmed poor survival rates in case of lower expression of the SDH subunits SDHB, SDHC and SDHD (16).…”

“…Functional deficiency of succinate dehydrogenase (SDH), resulting in succinate accumulation, is a common feature in up to 80% of ccRCCs (16). Survival analyses of the TCGA-KIRC dataset confirmed poor survival rates in case of lower expression of the SDH subunits SDHB, SDHC and SDHD (16). Notably, RCC tumors show a remarkable metabolic heterogeneity (17,18), however, still little is known how specific cellular components of the TME contribute to therapy response or resistance mechanisms.…”

“…FH catalyzes the conversion of fumarate to L-malate. Fumarate itself is the product of succinate oxidation by succinate dehydrogenase (16). The TCA cycle is fueled by acetyl-CoA, which condenses with oxaloacetate to form citrate in the first step of the pathway.…”

Effect of lipopolysaccharide (LPS) on HAEC cells. Does nicotinamide N-methyltransferase sensitize HAEC cells to LPS?

“…Interestingly silencing of the NNMT gene itself does not influence the level of metabolites but fumarate which concentration was substantially reduced. It could result from increased methylation of SDH gene promoter and reduced SDH transcription rate [Aggarwal et al, 2021, and for rev. Hawkins et al, 2018].…”