气候变化领域集成服务门户(CCPortal): Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer

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DOI	10.1073/pnas.2106947118
	Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer
	Aggarwal R.K.; Luchtel R.A.; Machha V.; Tischer A.; Zou Y.; Pradhan K.; Ashai N.; Ramachandra N.; Albanese J.M.; Yang J.-I.; Wang X.; Aluri S.; Gordon S.; Aboumohamed A.; Gartrell B.A.; Hafizi S.; Pullman J.; Shenoy N.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:39
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Kidney cancer; Succinate; Succinate dehydrogenase; TET-2
语种	英语
scopus关键词	ascorbic acid; hypoxia inducible factor; succinate dehydrogenase; 5 methylcytosine; SDHB protein, human; succinate dehydrogenase; tumor marker; Article; binding affinity; clear cell renal cell carcinoma; clinical feature; complex II deficiency; controlled study; disease exacerbation; down regulation; embryo; enzyme activity; human; human cell; pathogenesis; upregulation; von Hippel Lindau disease; apoptosis; cell cycle; cell motion; cell proliferation; chemistry; DNA methylation; gene expression regulation; genetic epigenesis; genetics; kidney tumor; metabolism; mutation; pathology; prognosis; renal cell carcinoma; survival rate; tumor cell culture; tumor invasion; 5-Methylcytosine; Apoptosis; Biomarkers, Tumor; Carcinoma, Renal Cell; Cell Cycle; Cell Movement; Cell Proliferation; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Mutation; Neoplasm Invasiveness; Prognosis; Succinate Dehydrogenase; Survival Rate; Tumor Cells, Cultured
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251010
作者单位	Department of Medicine (Oncology), Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, United States; InBios International Inc., Seattle, WA 98109, United States; Department of Medicine (Hematology), Mayo Clinic, Rochester, MN 55905, United States; Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, United States; Department of Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, NY 10461, United States; Department of Urology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, United States; Department of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2UP, United Kingdom; Experimental Therapeutics Program, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, United States; Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
推荐引用方式 GB/T 7714	Aggarwal R.K.,Luchtel R.A.,Machha V.,et al. Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer[J],2021,118(39).
APA	Aggarwal R.K..,Luchtel R.A..,Machha V..,Tischer A..,Zou Y..,...&Shenoy N..(2021).Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer.Proceedings of the National Academy of Sciences of the United States of America,118(39).
MLA	Aggarwal R.K.,et al."Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer".Proceedings of the National Academy of Sciences of the United States of America 118.39(2021).