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

Ritesh K. Aggarwal, Rebecca A. Luchtel, Venkata Machha, Alexander Tischer, Yiyu Zou, Kith Pradhan, Nadia Ashai, Nandini Ramachandra, Joseph M. Albanese, Jung-in Yang, Xiaoyang Wang, Srinivas Aluri, Shanisha Gordon, Ahmed Aboumohamed, Benjamin A. Gartrell, Sassan Hafizi, James Pullman, Niraj Shenoy

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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.
Original languageEnglish
Article numbere2106947118
Number of pages12
JournalProceedings of the National Academy of Sciences
Volume118
Issue number39
DOIs
Publication statusPublished - 28 Sep 2021

Keywords

  • succinate
  • succinate dehydrogenase
  • kidney cancer
  • TET-2

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