Research Papers:

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

Dudi Warsito _, Yingbo Lin, Ann-Christin Gnirck, Bita Sehat and Olle Larsson

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Oncotarget. 2016; 7:42288-42302. https://doi.org/10.18632/oncotarget.9785

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Dudi Warsito1, Yingbo Lin1, Ann-Christin Gnirck1, Bita Sehat1, Olle Larsson1

1Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-171 76 Stockholm, Sweden

Correspondence to:

Dudi Warsito, email: dudi.warsito@ki.se

Keywords: IGF-1R, phosphorylation, histone, SNAI2, Brg1

Received: July 28, 2015    Accepted: April 26, 2016    Published: June 02, 2016


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.

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