Nuclearly translocated insulin-like growth factor 1 receptor phosphorylates histone H3 at tyrosine 41 and induces SNAI2 expression via Brg1 chromatin remodeling protein

Oncotarget. 2016 Jul 5;7(27):42288-42302. doi: 10.18632/oncotarget.9785.


The insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase that has crucial roles in cell proliferation and protection from apoptosis. It is therefore not surprising that IGF-1R is often found overexpressed in many types of tumors. This has made IGF-1R a prominent target molecule for pharmacological companies to develop new anti-cancer agents. However, several clinical trials during the last 5 years using IGF-1R specific antibodies have shown disappointing results. We have previously shown that upon IGF-1 stimulation, the receptor becomes SUMOylated and translocates into the nucleus of cancer cells to act as a transcription co-factor. Soon after our original study, several others have reported nuclear IGF-1R (nIGF-1R) as well, and some of them have demonstrated a prognostic value of nIGF-1R expression in cancer. In the current study we demonstrate that nIGF-1R binds to and phosphorylates histone H3 at tyrosine 41 (H3Y41) in HeLa cells. Furthermore, our results suggest that phosphorylation of H3Y41 by nIGF-1R, stabilizes the binding of Brg1 chromatin remodeling protein to Histone H3. Our findings suggest that phosphorylated nIGF-1R, rather than total nIGF-1R, plays a superior role in these contexts. We identified SNAI2 oncogene as a target gene for nIGF-1R and its expression was decreased upon mutation of H3Y41 or by Brg1 knockdown. Furthermore, we demonstrate that both IGF-1R and Brg1 binds to the SNAI2 promoter. As SNAI2 protein is implicated in e.g. cancer invasion and metastasis, the nIGF-1R-mediated effects shown in this study may influence such important tumor phenotypic actions.

Keywords: Brg1; IGF-1R; SNAI2; histone; phosphorylation.

MeSH terms

  • Active Transport, Cell Nucleus
  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • Chromatin / chemistry
  • Chromatin Assembly and Disassembly
  • DNA Helicases / metabolism*
  • DNA, Complementary / metabolism
  • HeLa Cells
  • Histones / chemistry*
  • Humans
  • Ligands
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Binding
  • Receptor, IGF Type 1
  • Receptors, Somatomedin / metabolism*
  • Snail Family Transcription Factors / metabolism*
  • Transcription Factors / metabolism*
  • Tyrosine / chemistry*


  • Chromatin
  • DNA, Complementary
  • Histones
  • IGF1R protein, human
  • Ligands
  • Nuclear Proteins
  • Receptors, Somatomedin
  • SNAI2 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors
  • Tyrosine
  • Receptor, IGF Type 1
  • SMARCA4 protein, human
  • DNA Helicases