Myc-mediated SDHA acetylation triggers epigenetic regulation of gene expression and tumorigenesis.

Nature metabolism 2020 Mar

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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.

Citation

Shi-Ting Li, De Huang, Shengqi Shen, Yongping Cai, Songge Xing, Gongwei Wu, Zetan Jiang, Yijie Hao, Mengqiu Yuan, Nana Wang, Lianbang Zhu, Ronghui Yan, Dongdong Yang, Lin Wang, Zhaoji Liu, Xin Hu, Rongbin Zhou, Kun Qu, Ailing Li, Xiaotao Duan, Huafeng Zhang, Ping Gao. Myc-mediated SDHA acetylation triggers epigenetic regulation of gene expression and tumorigenesis. Nature metabolism. 2020 Mar;2(3):256-269