Sirt1 deacetylates c-Myc and promotes c-Myc/Max association

Int J Biochem Cell Biol. 2011 Nov;43(11):1573-81. doi: 10.1016/j.biocel.2011.07.006. Epub 2011 Jul 22.

Abstract

The c-Myc oncoprotein plays critical roles in multiple biological processes by controlling cell proliferation, apoptosis, differentiation, and metabolism. Especially, c-Myc is frequently overexpressed in many human cancers and widely involved in tumorigenesis. However, how the post-translational modifications, especially acetylation of c-Myc, contribute to its activity in the leukemia cells remains largely unknown. Sirt1, a NAD-dependent class III histone deacetylase, has a paradoxical role in tumorigenesis by deacetylating several transcription factors, including p53, E2F1 and forkhead proteins. In this study, we show that Sirt1 interacts physically with the C-terminus of c-Myc and deacetylates c-Myc both in vitro and in vivo. Moreover, the deacetylation of c-Myc by Sirt1 promotes its association with Max, a partner essential for its activation, thereby facilitating c-Myc transactivation activity on hTERT promoter. Finally, inhibition of endogenous Sirt1 in K562 cells by either RNAi or its inhibitor NAM causes the overall decrease of c-Myc target genes expression, including hTERT, cyclinD2 and LDHA, which further suppress cell proliferation and arrest cell cycle at G1/S phase. Thus, our results demonstrate the positive effect of Sirt1 on c-Myc activity by efficiently enhancing c-Myc/Max association in human leukemia cell line K562, suggesting a potential role of Sirt1 in tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cell Cycle Checkpoints
  • Cell Differentiation / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Humans
  • Immunoprecipitation
  • K562 Cells
  • Leukemia, Erythroblastic, Acute / genetics
  • Leukemia, Erythroblastic, Acute / metabolism*
  • Plasmids
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction / genetics*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Transcriptional Activation
  • Transfection

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • MAX protein, human
  • Proto-Oncogene Proteins c-myc
  • SIRT1 protein, human
  • Sirtuin 1