title: Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells.
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.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Forloni
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Romi
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Arvindhan
authors.initials: A
authors.lastname: Nagarajan
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Li-Sha
authors.initials: LS
authors.lastname: Sun
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pirazzoli
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Toki
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Wurtz
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Melnick
authors.affiliation: Department of Medicine, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02212, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: 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.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.affiliation: 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.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.affiliation: 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.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Gettinger
authors.affiliation: 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.
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
authors.affiliation: Singapore Institute of Clinical Sciences, Agency for Science, Technology, and Research, Brenner Center for Molecular Medicine, 30 Medical Drive, Singapore 117609, Singapore.
authors.forename: Shaillay Kumar
authors.initials: SK
authors.lastname: Dogra
authors.affiliation: 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.
authors.forename: Narendra
authors.initials: N
authors.lastname: Wajapeyee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D020935:MAP Kinase Signaling System; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009857:Oncogenes; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors