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

TY - JOUR

T1 - Nuclearly translocated insulin-like growth factor 1 receptor phosphorylates histone H3 at tyrosine 41 and induces SNAI2 expression via Brg1 chromatin remodeling protein

AU - Warsito, Dudi

AU - Lin, Yingbo

AU - Gnirck, Ann-Christin

AU - Sehat, Bita

AU - Larsson, Olle

PY - 2016/7/5

Y1 - 2016/7/5

N2 - 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.

AB - 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.

KW - Active Transport, Cell Nucleus

KW - Cell Line, Tumor

KW - Cell Nucleus/metabolism

KW - Chromatin/chemistry

KW - Chromatin Assembly and Disassembly

KW - DNA Helicases/metabolism

KW - DNA, Complementary/metabolism

KW - HeLa Cells

KW - Histones/chemistry

KW - Humans

KW - Ligands

KW - Neoplasm Invasiveness

KW - Neoplasm Metastasis

KW - Nuclear Proteins/metabolism

KW - Phosphorylation

KW - Protein Binding

KW - Receptors, Somatomedin/metabolism

KW - Snail Family Transcription Factors/metabolism

KW - Transcription Factors/metabolism

KW - Tyrosine/chemistry

U2 - 10.18632/oncotarget.9785

DO - 10.18632/oncotarget.9785

M3 - SCORING: Journal article

C2 - 27275536

VL - 7

SP - 42288

EP - 42302

JO - ONCOTARGET

JF - ONCOTARGET

SN - 1949-2553

IS - 27

ER -