The oncogenic transcription factor cMyc (or Myc) regulates up to 15% of the human genes involved in the cell cycle and cellular growth, apoptosis, differentiation and metabolism, as well as other key events, under diverse conditions. However, it is still unclear whether cMyc extensively regulates gene expression and tumor development through mechanisms other than transcription.

Recently, a group led by Prof. ZHANG Huafeng and Prof. GAO Ping from University of Science and Technology of China of the Chinese Academy of Sciences, collaborating with DUAN Xiaotao from State Key Laboratory of Toxicology and Medical Countermeasures, revealed that acetylation-dependent SDH-complex deactivation is critical for Myc-driven epigenetic regulation of gene expression and tumorigenesis. This study was published online in Nature Metabolism.

The researchers showed that by deactivating succinate dehydrogenase complex subunit A (SDHA) via acetylation, Myc triggers a regulatory cascade in cancer cells that leads to trimethylated histone H3 Lys 4 (H3K4me3) activation and gene expression. They found that Myc facilitates the acetylation-dependent deactivation of SDHA by activating the SKP2-mediated degradation of SIRT3 deacetylase.

Besides, the researchers demonstrated that Myc inhibition of SDH-complex activity leads to cellular succinate accumulation, which triggers H3K4me3 activation and tumour-specific gene expression. They found that acetylated SDHA at Lys 335 contributes to tumour growth in vitro and in vivo, and confirmed increased tumorigenesis in clinical samples.

SDHA is considered to be a tumor suppressor protein, and its inactive mutant has a certain degree of connection with many tumors, such as paraneoplastic tumors and kidney cancer. The research results showed that SDHA greatly promotes the progression of cMyc abnormally expressed tumors through inactive acetylation, at least in diffuse large B-cell lymphomas.

This study illustrates a link between acetylation-dependent SDHA deactivation and Myc-driven epigenetic regulation of gene expression, which is critical for cancer progression.

Myc-mediated SDHA acetylation and H3K4me3 activation trigger epigenetic regulation of gene expression and tumorigenesis. (Image by LI Shiting's group)