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.

之前认为琥珀酸脱氢酶 (SDH) 活性降低导致不利的琥珀酸积累，仅与 0.05% 至 0.5% 的与生殖系 SDH 突变相关的肾癌相关。在这里，我们试图检查 SDH 丢失在肾癌发病机制/进展中的更广泛作用。我们报告说，SDH 亚基的低表达导致致癌琥珀酸的积累是透明细胞肾细胞癌 (ccRCC)（所有肾癌的约 80%）的一个共同特征，对 ccRCC 患者的生存有显着的不利影响（n= 516）。我们表明，在 ccRCC 发病机制和进展过程中，SDH 下调是 TCA 循环中的关键刹车。在探索 ccRCC 中 SDH 下调的机制时，我们报告了 Von Hippel-Lindau 缺失诱导的缺氧诱导因子依赖性 miR-210 上调导致SDHD转录物的直接抑制。此外，SDHB的浅删除约 20% 的 ccRCC 发生。然后，我们证明 SDH 丢失诱导的琥珀酸积累导致 5-羟甲基胞嘧啶的不利丢失、5-甲基胞嘧啶的增加以及通过抑制 10-11 易位 (TET)-2 活性增强 ccRCC 的侵袭性。有趣的是，发现重组 TET-2 的催化结构域与琥珀酸之间的结合亲和力非常低，这表明琥珀酸诱导 TET-2 活性减弱的机制可能是通过产物抑制而不是竞争性抑制。最后，外源性抗坏血酸（一种 TET 激活去甲基化剂）导致琥珀酸在 ccRCC 细胞中的上述致癌作用逆转。总的来说，