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

Fei Yan, Na Shen, Jiuxia Pang, Julian R Molina, Ping Yang, Shujun Liu

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19 Scopus citations


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 (decitabineR) or PKC412 (PKC412R) eventually results from simultaneously remethylated DNA and reactivated kinase cascades. Indeed, both decitabineRand PKC412R 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, decitabineR and PKC412R 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 decitabineR or PKC412R cell proliferation. Further, DNMT1 knockdown sensitized PKC412R cells to PKC412; conversely, KIT depletion synergized with decitabine in eliminating decitabineR. Importantly, when engrafted into nude mice, decitabineR and PKC412R 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.

Original languageEnglish (US)
Pages (from-to)18480-18494
Number of pages15
JournalJournal of Biological Chemistry
Issue number30
StatePublished - Jul 24 2015


ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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