Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer
Ritesh K. Aggarwal, Rebecca A. Luchtel, Venkata R. Machha, Alexander Tischer, Yiyu Zou, Kith Pradhan, Nadia Ashai, Nandini Ramachandra, Joseph Albanese, Jung‐In Yang, Xiaoyang Wang, Srinivas Aluri, Shanisha Gordon, Ahmed Aboumohamed, Benjamin A. Gartrell, Sassan Hafizi, James Pullman, Niraj Shenoy
Abstract
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.