ArticleThe Journal of biological chemistry2015
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.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 33 citations in OpenAlex.
- DNMT1 is associated with QDPR downregulation and chemotherapy response in lung adenocarcinoma.Medical oncology (Northwood, London, England) · 2026Article
- Novel therapeutic targets at the crossroad between epigenetics and signal transduction pathways in B-cell lymphomas.Clinical and experimental medicine · 2026Review
- Unravelling chemotherapeutic activity of fisetin ruthenium-p-cymene complex in lung cancer treatment by the modulation of GRB2/RAS/MEK/DNMT1 signaling pathway.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Immune-related gene methylation prognostic instrument for stratification and targeted treatment of ovarian cancer patients toward advanced 3PM approach.The EPMA journal · 2024Article
- Coordinated activation of DNMT3a and TET2 in cancer stem cell-like cells initiates and sustains drug resistance in hepatocellular carcinoma.Cancer cell international · 2024Article
- Thymoquinone Enhances Apoptosis of K562 Chronic Myeloid Leukemia Cells through Hypomethylation ofPharmaceuticals (Basel, Switzerland) · 2023Article
- The Epigenesis of Salivary Glands Carcinoma: From Field Cancerization to Carcinogenesis.Cancers · 2023Review
- Pleomorphic Adenoma of the Salivary Glands and Epithelial-Mesenchymal Transition.Journal of clinical medicine · 2022Review
- Thymoquinone Inhibits Growth of Acute Myeloid Leukemia Cells through ReversalPharmaceuticals (Basel, Switzerland) · 2021Article
- An Assessment on Ethanol-Blended Gasoline/Diesel Fuels on Cancer Risk and Mortality.International journal of environmental research and public health · 2021Review
- Multifunctional Gold Nanoparticles Overcome MicroRNA Regulatory Network Mediated-Multidrug Resistant Leukemia.Scientific reports · 2019Article
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- Review
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- The enhancement of combination of berberine and metformin in inhibition of DNMT1 gene expression through interplay of SP1 and PDPK1.Journal of cellular and molecular medicine · 2018Article
- A regulatory circuit composed of DNA methyltransferases and receptor tyrosine kinases controls lung cancer cell aggressiveness.Oncogene · 2017Article
- Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Article
- Thymoquinone exerts potent growth-suppressive activity on leukemia through DNA hypermethylation reversal in leukemia cells.Oncotarget · 2017Article
- Inhibition of EZH2 via activation of SAPK/JNK and reduction of p65 and DNMT1 as a novel mechanism in inhibition of human lung cancer cells by polyphyllin I.Journal of experimental & clinical cancer research : CR · 2016Article
- Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells.PloS one · 2016Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.