title: EZH2 inhibition enhances the efficacy of an EGFR inhibitor in suppressing colon cancer cells.
abstract: Metastatic colon cancer has a 5-year survival of less than 10% despite the use of aggressive chemotherapeutic regimens. As signaling from epidermal growth factor receptor (EGFR) is often enhanced and epigenetic regulation is often altered in colon cancer, it is desirable to enhance the efficacy of EGFR-directed therapy by co-targeting an epigenetic pathway. We showed that the histone methyltransferase EZH2, which catalyzes methylation of histone H3 lysine 27 (H3K27), was upregulated in colon cancers in The Cancer Genome Atlas (TCGA) database. Since co-inhibition of both EGFR and EZH2 has not been studied in colon cancer, we examined the effects of co-inhibition of EGFR and EZH2 on 2 colon cancer cell lines, HT-29 and HCT-15. Co-inhibition of EZH2 and EGFR with the small molecules UNC1999 and gefitinib, led to a significant decrease in cell number and increased apoptosis compared to inhibition of either pathway alone, and similar results were noted after EZH2 shRNA knockdown. Moreover, co-inhibition of EZH2 and EGFR also significantly induced autophagy, indicating that autophagy may play a role in the observed synergy. Together, these findings suggest that inhibition of both EZH2 and EGFR serves as an effective method to increase the efficacy of EGFR inhibitors in suppressing colon cancer cells.
authors.affiliation: a Division of Gastroenterology; University of Pennsylvania Perelman School of Medicine ; Philadelphia , PA USA.
authors.forename: Bryson W
authors.initials: BW
authors.lastname: Katona
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Anqi
authors.initials: A
authors.lastname: Ma
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Xianxin
authors.initials: X
authors.lastname: Hua
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D000071221:Enhancer of Zeste Homolog 2 Protein; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D015870:Gene Expression; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR; EGFR, epidermal growth factor receptor; EZH2; H3K27, histone H3 lysine 27; HDAC, histone deacetylase; PRC2, polycomb repressive complex 2; TCGA, The Cancer Genome Atlas; UNC1999; autophagy; colon cancer; epigenetics; gefitinib