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

Nature Metabolism
Shi-Ting LiPing Gao

Abstract

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.

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Datasets Mentioned

BETA
GSE124255

Methods Mentioned

BETA
acetylation
immunoprecipitation
immunoprecipitation assay
dot blot assay
acetylating
ubiquitination
ChIP-seq
ChIP
RNA-seq
PCR

Software Mentioned

Proteome Discovery
DAVID
Sciex Analyst
MasterView
Bowtie2
Sciex PeakView
IGV
MASCOT
MultiQuant
TopHat2

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