ArticleCell death & disease2021
Suppression of m6A mRNA modification by DNA hypermethylated ALKBH5 aggravates the oncological behavior of KRAS mutation/LKB1 loss lung cancer.
Article in Cell death & disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 67 citations in OpenAlex.
- Article
- KRAS and MYC synergistic inhibition: a powerful strategy targeting KRAS-mutant cancers.Molecular cancer · 2026Review
- TRMT6-directed mNPJ precision oncology · 2026Article
- Review
- piR-hsa-022095 Drives Hypertrophic Scar Formation via KLF11-Dependent Fibroblast Proliferation.Biomedicines · 2025Article
- M6A-ALKBH5-dependent RBMS3-AS3 down-regulation suppresses ferroptosis to promote lung adenocarcinoma progression through HNRNPDL/ZEB1/GPX4 axis.NPJ precision oncology · 2025Article
- mMolecules (Basel, Switzerland) · 2025Review
- ALKBH5 suppresses mOncogene · 2025Article
- Exploring the methyl-verse: Dynamic interplay of epigenome and m6A epitranscriptome.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer.The Journal of clinical investigation · 2025Article
- The roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy.Molecular cancer · 2025Review
- Interactions between ALKBH5 and reader proteins in tumors: functions and molecular mechanisms.Frontiers in oncology · 2025Review
- The therapeutic potential of RNA m(6)A in lung cancer.Cell communication and signaling : CCS · 2024Review
- Insights into the mCell & bioscience · 2024Review
- Cancer metastases: Tailoring the targets.Heliyon · 2024Review
- Role of N6-methyladenosine in tumor neovascularization.Cell death & disease · 2024Review
- Landscape of mFrontiers in pharmacology · 2024Review
- FTO facilitates cancer metastasis by modifying the mCell communication and signaling : CCS · 2023Article
- The role of m6A demethylases in lung cancer: diagnostic and therapeutic implications.Frontiers in immunology · 2023Review
- N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms.Frontiers in immunology · 2023Review
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Oncogenic KRAS mutations combined with the loss of the LKB1 tumor-suppressor gene (KL) are strongly associated with aggressive forms of lung cancer. N6-methyladenosine (m6A) in mRNA is a crucial epigenetic modification that controls cancer self-renewal and progression. However, the regulation and role of m6A modification in this cancer are unclear. We found that decreased m6A levels correlated with the disease progression and poor survival for KL patients. The correlation was mediated by a special increase in ALKBH5 (AlkB family member 5) levels, an m6A demethylase. ALKBH5 gain- or loss-of function could effectively reverse LKB1 regulated cell proliferation, colony formation, and migration of KRAS-mutated lung cancer cells. Mechanistically, LKB1 loss upregulated ALKBH5 expression by DNA hypermethylation of the CTCF-binding motif on the ALKBH5 promoter, which inhibited CTCF binding but enhanced histone modifications, including H3K4me3, H3K9ac, and H3K27ac. This effect could successfully be rescued by LKB1 expression. ALKBH5 demethylation of m6A stabilized oncogenic drivers, such as SOX2, SMAD7, and MYC, through a pathway dependent on YTHDF2, an m6A reader protein. The above findings were confirmed in clinical KRAS-mutated lung cancer patients. We conclude that loss of LKB1 promotes ALKBH5 transcription by a DNA methylation mechanism, reduces m6A modification, and increases the stability of m6A target oncogenes, thus contributing to aggressive phenotypes of KRAS-mutated 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.