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Cell Rep. 2016 Jul 12;16(2):457-471. doi: 10.1016/j.celrep.2016.05.087. Epub 2016 Jun 23.

Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
2
Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
3
Department of Medicine, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02212, USA.
4
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
5
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Medicine and Medical Oncology, Yale University School of Medicine, New Haven, CT 06510, USA.
6
Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Medicine and Medical Oncology, Yale University School of Medicine, New Haven, CT 06510, USA.
7
Singapore Institute of Clinical Sciences, Agency for Science, Technology, and Research, Brenner Center for Molecular Medicine, 30 Medical Drive, Singapore 117609, Singapore.
8
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: narendra.wajapeyee@yale.edu.

Abstract

Oncogene-induced DNA methylation-mediated transcriptional silencing of tumor suppressors frequently occurs in cancer, but the mechanism and functional role of this silencing in oncogenesis are not fully understood. Here, we show that oncogenic epidermal growth factor receptor (EGFR) induces silencing of multiple unrelated tumor suppressors in lung adenocarcinomas and glioblastomas by inhibiting the DNA demethylase TET oncogene family member 1 (TET1) via the C/EBPα transcription factor. After oncogenic EGFR inhibition, TET1 binds to tumor suppressor promoters and induces their re-expression through active DNA demethylation. Ectopic expression of TET1 potently inhibits lung and glioblastoma tumor growth, and TET1 knockdown confers resistance to EGFR inhibitors in lung cancer cells. Lung cancer samples exhibited reduced TET1 expression or TET1 cytoplasmic localization in the majority of cases. Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors that may have therapeutic benefits for oncogenic EGFR-mediated lung cancers and glioblastomas.

PMID:
27346347
PMCID:
PMC4945411
DOI:
10.1016/j.celrep.2016.05.087
[Indexed for MEDLINE]
Free PMC Article

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