Nuclearly translocated insulin-like growth factor 1 receptor phosphorylates histone H3 at tyrosine 41 and induces SNAI2 expression via Brg1 chromatin remodeling protein.
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.
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Dudi
D
Warsito
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Yingbo
Y
Lin
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Ann-Christin
AC
Gnirck
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Bita
B
Sehat
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Olle
O
Larsson
D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000737:chemistry; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry*
D002843:Chromatin; D018076:DNA, Complementary; D006657:Histones; C000597236:IGF1R protein, human; D008024:Ligands; D009687:Nuclear Proteins; D017451:Receptors, Somatomedin; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014443:Tyrosine; D017526:Receptor, IGF Type 1; C084108:SMARCA4 protein, human; D004265:DNA Helicases
Brg1; IGF-1R; SNAI2; histone; phosphorylation