Editors' ChoiceCancer

Going Nuclear with EGFR

Science Signaling  05 Aug 2014:
Vol. 7, Issue 337, pp. ec205
DOI: 10.1126/scisignal.2005761

Although usually thought of only as cell surface receptors, many receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR), also function in the nucleus. Both ionizing radiation (IR) and the ligand EGF stimulate translocation of EGFR to the nucleus, where it affects gene transcription and DNA synthesis and repair. Chou et al. report that both IR and EGF triggered colocalization of EGFR and histone H4 in the nuclei of cultured A431 cervical cancer and MDA-MB-468 breast cancer cells. EGFR and H4 coimmunoprecipitated from extracts of these cells, and EGFR phosphorylated H4 on Tyr72 in vitro and promoted this phosphorylation in cultured cells. EGFR-mediated phosphorylation of H4 on Tyr72 recruited the histone methyltransferases SET8 and SUV4-20H to H4 and promoted both mono- and dimethylation of H4 on Lys20 in cells. SET8-mediated monomethylation of H4 on Lys20 is required for DNA synthesis, and SUV4-20H–mediated dimethylation of this residue is required for DNA repair. EGF promoted DNA synthesis in cells that had wild-type H4, but not in cells that had mutant forms of H4 in which Tyr72 or Lys20 had been mutated (H4Y72F and H4K20R). Repair of double-strand DNA breaks induced by IR was reduced in cells with H4Y72F compared to cells with wild-type H4. Increased EGFR signaling is implicated in several types of human tumors, including breast cancer. A peptide that competed with H4 for binding to EGFR reduced tumor size in an MDA-MB-468 breast cancer xenograft model. By immunohistochemical staining of human breast tumor samples, the abundance of EGFR positively correlated with the abundance of Tyr72-phosphorylated and Lys20-methylated H4 and with a marker of cell proliferation in human breast tumor samples. This potential for nuclear EGFR to promote DNA synthesis and repair in cancer cells may therefore have implications for the survival and proliferation of tumor cells.

R. -H. Chou, Y. -N. Wang, Y. -H. Hsieh, L. -Y. Li, W. Xia, W. -C. Chang, L. -C. Chang, C. -C. Cheng, C. -C. Lai, J. L. Hsu, W. -J. Chang, S. -Y. Chiang, H. -J. Lee, H. -W. Liao, P. -H. Chuang, H. -Y. Chen, H. -L. Wang, S. -C. Kuo, C.- H. Chen, Y. -L. Yu, M. -C. Hung, EGFR modulates DNA synthesis and repair through Tyr phosphorylation of histone H4. Dev. Cell 30, 224–237 (2014). [PubMed]