Sin3b interacts with Myc and decreases Myc levels

J Biol Chem. 2014 Aug 8;289(32):22221-36. doi: 10.1074/jbc.M113.538744. Epub 2014 Jun 20.

Abstract

Myc expression is deregulated in many human cancers. A yeast two-hybrid screen has revealed that the transcriptional repressor Sin3b interacts with Myc protein. Endogenous Myc and Sin3b co-localize and interact in the nuclei of human and rat cells, as assessed by co-immunoprecipitation, immunofluorescence, and proximity ligation assay. The interaction is Max-independent. A conserved Myc region (amino acids 186-203) is required for the interaction with Sin3 proteins. Histone deacetylase 1 is recruited to Myc-Sin3b complexes, and its deacetylase activity is required for the effects of Sin3b on Myc. Myc and Sin3a/b co-occupied many sites on the chromatin of human leukemia cells, although the presence of Sin3 was not associated with gene down-regulation. In leukemia cells and fibroblasts, Sin3b silencing led to Myc up-regulation, whereas Sin3b overexpression induced Myc deacetylation and degradation. An analysis of Sin3b expression in breast tumors revealed an association between low Sin3b expression and disease progression. The data suggest that Sin3b decreases Myc protein levels upon Myc deacetylation. As Sin3b is also required for transcriptional repression by Mxd-Max complexes, our results suggest that, at least in some cell types, Sin3b limits Myc activity through two complementary activities: Mxd-dependent gene repression and reduction of Myc levels.

Keywords: Breast Cancer; Gene Expression; Histone Deacetylase (HDAC); Myc (c-Myc); Sin3b; Transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / metabolism
  • Disease Progression
  • Down-Regulation
  • Female
  • Genes, myc
  • HEK293 Cells
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Humans
  • K562 Cells
  • Middle Aged
  • Models, Biological
  • Protein Interaction Domains and Motifs
  • Proteolysis
  • Proto-Oncogene Proteins c-myc / chemistry
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Rats
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcriptional Activation
  • Two-Hybrid System Techniques

Substances

  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins
  • SIN3B protein, human
  • HDAC1 protein, human
  • Histone Deacetylase 1