SETD6 controls the expression of estrogen-responsive genes and proliferation of breast carcinoma cells

Epigenetics. 2014 Jul;9(7):942-50. doi: 10.4161/epi.28864. Epub 2014 Apr 21.


The lysine methyltransferase SETD6 modifies the histone variant H2AZ, a key component of nuclear receptor-dependent transcription. Herein, we report the identification of several factors that associate with SETD6 and are implicated in nuclear hormone receptor signaling. Specifically, SETD6 associates with the estrogen receptor α (ERα), histone deacetylase HDAC1, metastasis protein MTA2, and the transcriptional co-activator TRRAP. Luciferase reporter assays identify SETD6 as a transcriptional repressor, in agreement with its association with HDAC1 and MTA2. However, SETD6 behaves as a co-activator of several estrogen-responsive genes, such as PGR and TFF1. Consistent with these results, silencing of SETD6 in several breast carcinoma cell lines induced cellular proliferation defects accompanied by enhanced expression of the cell cycle inhibitor CDKN1A and induction of apoptosis. Herein, we have identified several chromatin proteins that associate with SETD6 and described SETD6 as an essential factor for nuclear receptor signaling and cellular proliferation.

Keywords: SETD6; cellular proliferation; estrogen receptor; lysine methyltransferase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation*
  • Chromatin / genetics
  • Chromatin / metabolism
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogens / metabolism*
  • Female
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Protein Methyltransferases / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Transcription, Genetic


  • Chromatin
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogens
  • Nuclear Proteins
  • Repressor Proteins
  • Protein Methyltransferases
  • SETD6 protein, human
  • MTA2 protein, human
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases