title: The DNA Methyltransferase DNMT1 and Tyrosine-Protein Kinase KIT Cooperatively Promote Resistance to 5-Aza-2'-deoxycytidine (Decitabine) and Midostaurin (PKC412) in Lung Cancer Cells.
abstract: Lung cancer cells are sensitive to 5-aza-2'-deoxycytidine (decitabine) or midostaurin (PKC412), because decitabine restores the expression of methylation-silenced tumor suppressor genes, whereas PKC412 inhibits hyperactive kinase signaling, which is essential for cancer cell growth. Here, we demonstrated that resistance to decitabine (decitabine(R)) or PKC412 (PKC412(R)) eventually results from simultaneously remethylated DNA and reactivated kinase cascades. Indeed, both decitabine(R) and PKC412(R) displayed the up-regulation of DNA methyltransferase DNMT1 and tyrosine-protein kinase KIT, the enhanced phosphorylation of KIT and its downstream effectors, and the increased global and gene-specific DNA methylation with the down-regulation of tumor suppressor gene epithelial cadherin CDH1. Interestingly, decitabine(R) and PKC412(R) had higher capability of colony formation and wound healing than parental cells in vitro, which were attributed to the hyperactive DNMT1 or KIT, because inactivation of KIT or DNMT1 reciprocally blocked decitabine(R) or PKC412(R) cell proliferation. Further, DNMT1 knockdown sensitized PKC412(R) cells to PKC412; conversely, KIT depletion synergized with decitabine in eliminating decitabine(R). Importantly, when engrafted into nude mice, decitabine(R) and PKC412(R) had faster proliferation with stronger tumorigenicity that was caused by the reactivated KIT kinase signaling and further CDH1 silencing. These findings identify functional cross-talk between KIT and DNMT1 in the development of drug resistance, implying the reciprocal targeting of protein kinases and DNA methyltransferases as an essential strategy for durable responses in lung cancer.
authors.affiliation: From the Hormel Institute, University of Minnesota, Austin, Minnesota 55912 and.
authors.forename: Fei
authors.initials: F
authors.lastname: Yan
authors.affiliation: From the Hormel Institute, University of Minnesota, Austin, Minnesota 55912 and.
authors.forename: Na
authors.initials: N
authors.lastname: Shen
authors.affiliation: From the Hormel Institute, University of Minnesota, Austin, Minnesota 55912 and.
authors.forename: Jiuxia
authors.initials: J
authors.lastname: Pang
authors.affiliation: the Department of Medical Oncology and.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.affiliation: the Division of Epidemiology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: From the Hormel Institute, University of Minnesota, Austin, Minnesota 55912 and sliu@hi.umn.edu.
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D019311:Staurosporine; C059539:midostaurin; D001374:Azacitidine
keywords: DNA methyltransferase; drug resistance; lung cancer; protein kinase; tumor suppressor gene