The transcriptional role of cMyc (or Myc) in tumorigenesis is well appreciated; however, it remains to be fully established how extensively Myc is involved in the epigenetic regulation of gene expression. Here, we show that by deactivating succinate dehydrogenase complex subunit A (SDHA) via acetylation, Myc triggers a regulatory cascade in cancer cells that leads to H3K4me3 activation and gene expression. We find that Myc facilitates the acetylation-dependent deactivation of SDHA by activating the SKP2-mediated degradation of SIRT3 deacetylase. We further demonstrate that Myc inhibition of SDH-complex activity leads to cellular succinate accumulation, which triggers H3K4me3 activation and tumour-specific gene expression. We demonstrate that acetylated SDHA at Lys 335 contributes to tumour growth in vitro and in vivo, and we confirm increased tumorigenesis in clinical samples. This study illustrates a link between acetylation-dependent SDHA deactivation and Myc-driven epigenetic regulation of gene expression, which is critical for cancer progression.

cMyc（或Myc）在肿瘤发生中的转录作用已广为人知；但是，Myc如何广泛参与基因表达的表观遗传调控尚待完全确定。在这里，我们显示了通过乙酰化使琥珀酸脱氢酶复合物亚基A（SDHA）失活，Myc触发了癌细胞中的调节级联反应，从而导致H3K4me3激活和基因表达。我们发现Myc通过激活SKP2介导的SIRT3脱乙酰基酶的降解来促进SDHA的乙酰化依赖性失活。我们进一步证明Myc对SDH复合物活性的抑制导致细胞琥珀酸积累，从而触发H3K4me3激活和肿瘤特异性基因表达。我们证明了Lys 335处的乙酰化SDHA有助于体内外的肿瘤生长，并且我们确认临床样本中的肿瘤发生增加。这项研究说明了乙酰化依赖的SDHA失活与Myc驱动的基因表达的表观遗传调控之间的联系，这对癌症的进展至关重要。