title: Epigenetic downregulation of RUNX3 by DNA methylation induces docetaxel chemoresistance in human lung adenocarcinoma cells by activation of the AKT pathway.
abstract: The RUNX3 gene has been shown to function as a tumor suppressor gene implicated in various cancers, but its association with tumor chemoresistance has not been fully understood. Here, we investigated the effect of epigenetic downregulation of RUNX3 in docetaxel resistance of human lung adenocarcinoma and its possible molecular mechanisms. RUNX3 was found to be downregulated by hypermethylation in docetaxel-resistant lung adenocarcinoma cells. Its overexpression could resensitize cells to docetaxel both in vitro and in vivo by growth inhibition, enhancement of apoptosis and G1 phase arrest. Conversely, knockdown of RUNX3 could lead to the decreased sensitivity of parental human lung adenocarcinoma cells to docetaxel by enhancing proliferative capacity. Furthermore, we showed that overexpression of RUNX3 could inactivate the AKT/GSK3β/β-catenin signaling pathway in the docetaxel-resistant cells. Importantly, co-transfection of RUNX3 and constitutively active Akt1 could reverse the effects of RUNX3 overexpression, while treatment with the MK-2206 (AKT inhibitor) mimicked the effects of RUNX3 overexpression in docetaxel-resistant human lung adenocarcinoma cells. Immunohistochemical analysis revealed that decreased RUNX3 expression was correlated with high expression of Akt1 and decreased sensitivity of patients to docetaxel-based chemotherapy. Taken together, our results suggest that epigenetic downregulation of RUNX3 can induce docetaxel resistance in human lung adenocarcinoma cells by activating AKT signaling and increasing expression of RUNX3 may represent a promising strategy for reversing docetaxel resistance in the future.
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University, 305 Zhongshan East Road, Nanjing 210002, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zheng
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Hai-Zhu
authors.initials: HZ
authors.lastname: Song
authors.forename: Ban-Zhou
authors.initials: BZ
authors.lastname: Pan
authors.forename: You-Wei
authors.initials: YW
authors.lastname: Zhang
authors.forename: Long-Bang
authors.initials: LB
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D000077143:Docetaxel; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; C493729:Runx3 protein, human; D043823:Taxoids; D000077143:Docetaxel; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; Chemoresistance; DNA methylation; Docetaxel; RUNX3