TY - JOUR
T1 - Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer
AU - Aggarwal, Ritesh K.
AU - Luchtel, Rebecca A.
AU - Machha, Venkata
AU - Tischer, Alexander
AU - Zou, Yiyu
AU - Pradhan, Kith
AU - Ashai, Nadia
AU - Ramachandra, Nandini
AU - Albanese, Joseph M.
AU - Yang, Jung In
AU - Wang, Xiaoyang
AU - Aluri, Srinivas
AU - Gordon, Shanisha
AU - Aboumohamed, Ahmed
AU - Gartrell, Benjamin A.
AU - Hafizi, Sassan
AU - Pullman, James
AU - Shenoy, Niraj
N1 - Funding Information:
We acknowledge the ccRCC metabolomic repository generated by MSKCC (3) and made publicly available via supplemental attachments. The metabolite data in Fig. 2 A, B, D, E, G, and H of this manuscript were derived from analysis of this repository. We acknowledge The Cancer Genome Atlas (TCGA) (https://www.cancer.gov/tcga) (55). We also acknowledge interactive Web-based platforms for analysis of the TCGA database: GEPIA (45), Xena (49), TCGA Wanderer (46), The Cancer Omics Atlas (50), UALCAN (51), CVCDAP (52), and GSEA pathway analysis software (47). We acknowledge Albert Einstein Cancer Center core grant startup (to N.S.) 2P30CA013330-47; American Cancer Society Research Scholar Grant RSG-20-137-01 TBG (to N.S.); and 2017 American Society of Hematology Research Award (to N.S.).
Funding Information:
ACKNOWLEDGMENTS. We acknowledge the ccRCC metabolomic repository generated by MSKCC (3) and made publicly available via supplemental attachments. The metabolite data in Fig. 2 A, B, D, E, G, and H of this manuscript were derived from analysis of this repository. We acknowledge The Cancer Genome Atlas (TCGA) (https://www.cancer.gov/tcga) (55). We also acknowledge interactive Web-based platforms for analysis of the TCGA database: GEPIA (45), Xena (49), TCGA Wanderer (46), The Cancer Omics Atlas (50), UALCAN (51), CVCDAP (52), and GSEA pathway analysis software (47). We acknowledge Albert Einstein Cancer Center core grant startup (to N.S.) 2P30CA013330-47; American Cancer Society Research Scholar Grant RSG-20-137-01 TBG (to N.S.); and 2017 American Society of Hematology Research Award (to N.S.).
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/9/28
Y1 - 2021/9/28
N2 - 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.
AB - 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.
KW - Kidney cancer
KW - Succinate
KW - Succinate dehydrogenase
KW - TET-2
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U2 - 10.1073/pnas.2106947118
DO - 10.1073/pnas.2106947118
M3 - Article
C2 - 34551979
AN - SCOPUS:85115797960
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 39
M1 - e2106947118
ER -