KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1118227 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29234800_1.fastq.gz | Fastqsanger.gz | |||
| SRR29234800_2.fastq.gz | Fastqsanger.gz | |||
| SRR29234801_1.fastq.gz | Fastqsanger.gz | |||
| SRR29234801_2.fastq.gz | Fastqsanger.gz | |||
| SRR29234802_1.fastq.gz | Fastqsanger.gz |
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Project description:Constitutively active mutations of KRAS frequently occur in non-small cell lung adenocarcinoma cells (NSCLC). However, the relationship between KRAS constitutive mutations and platinum drug resistance in NSCLC, as well as the underlying mechanism, remains unclear. In this study, we have identified that KRAS constitutive mutations confer resistance to platinum-based drugs in NSCLC. Mechanistically, KRAS mediates platinum resistance in NSCLC cells by enhancing ERK/JNK signaling, which controls post-translational modifications (PTMs) of ALKBH5. This, in turn, leads to an upregulation of m6A methylation in mRNA transcripts related to DNA repair genes. Consequently, the increased m6A methylation of these transcripts results in their mRNA stabilization, thereby protecting NSCLC cells from platinum-induced DNA damage and apoptosis, ultimately conferring platinum drug resistance in NSCLC. Furthermore, our observations indicate that blocking the KRAS mutation-induced increase in m6A methylation of DNA repair-related genes can sensitize NSCLC cells harboring KRAS mutations to platinum exposure. This can be achieved either by overexpressing a SUMOylation-deficient mutant of ALKBH5 or by pharmacologically inhibiting METTL3 enzymatic activity using a small molecule. These interventions significantly enhance the sensitivity of KRAS mutant-bearing NSCLC cells to platinum-based treatments both in vitro and in vivo. In summary, our study uncovers a previously unrecognized mechanism involving KRAS mutations, ALKBH5 PTMs, and increased mRNA m6A levels in DNA repair-related genes, which collectively promote platinum resistance in NSCLC cells.
2025-02-19 | GSE268671 | GEO
Project description:Constitutively active mutations of KRAS are prevalent in non-small cell lung cancer (NSCLC). However, the relationship between these mutations and resistance to platinum-based chemotherapy and the underlying mechanisms remain elusive. In this study, we demonstrate that KRAS mutants confer resistance to platinum in NSCLC. Mechanistically, KRAS mutants mediate platinum resistance in NSCLC cells by activating ERK/JNK signaling, which inhibits AlkB homolog 5 (ALKBH5) N6-methyladenosine (m6A) demethylase activity by regulating posttranslational modifications (PTMs) of ALKBH5. Consequently, the KRAS mutant leads to a global increase in m6A methylation of mRNAs, particularly damage-specific DNA-binding protein 2 (DDB2) and XPC, which are essential for nucleotide excision repair. This methylation stabilized the mRNA of these 2 genes, thus enhancing NSCLC cells' capability to repair platinum-induced DNA damage and avoid apoptosis, thereby contributing to drug resistance. Furthermore, blocking KRAS-mutant-induced m6A methylation, either by overexpressing a SUMOylation-deficient mutant of ALKBH5 or by inhibiting methyltransferase-like 3 (METTL3) pharmacologically, significantly sensitizes KRAS-mutant NSCLC cells to platinum drugs in vitro and in vivo. Collectively, our study uncovers a mechanism that mediates KRAS-mutant-induced chemoresistance in NSCLC cells by activating DNA repair through the modulation of the ERK/JNK/ALKBH5 PTM-induced m6A modification in DNA damage repair-related genes.
| S-EPMC11910214 | biostudies-literature
Project description:N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as a new mammalian demethylase that oxidatively removes the m6A modification in mRNA in vitro and inside cells. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1552 differentially expressed genes which cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. We show that Alkbh5-deficiency impacts the expression levels of some of these mRNAs, supporting the observed phenotype. The discovery of this new RNA demethylase strongly suggests that the reversible m6A modification plays fundamental and broad functions in mammalian cells. RNA-seq in two cell types
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Project description:Platinum-based chemotherapies are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a comprehensive, reproducible data resource comprised of dynamic (+/-carboplatin) proteomic/posttranslational modification and RNASeq profiles from HGSOC intra-patient cell line pairs derived from 3 patients before and after acquiring platinum resistance. The molecular profiles revealed extensive responses to carboplatin and differential responses between sensitive and resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that both pharmacologic inhibition and CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO is a candidate therapeutic target to overcome platinum resistance.
2022-01-04 | GSE163152 | GEO
Project description:The interacted proteins of ALKBH5 and FTO identified by IP-mass
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Project description:Neutrophils are key immune components in rheumatoid arthritis (RA), but the role of ALKBH5 in neutrophil function and RA progression remains unclear. METTL3, METTL14, WTAP, ALKBH5, FTO, YTHDF2, autophagy related gene were investigated by RT-qPCR. Autophagy, LC3B were respectively detected by flow cytometry analysis, Western blotting. Correlation analyses between ALKBH5 levels and RA disease activity, autophagy were performed, and receiver operating characteristic (ROC) curves were constructed to evaluate its predictive value. Univariate analysis and multivariate regression analysis were used to analyze the risk factors and construct predictive model. Sh-ALKBH5 lentiviral vectors was constructed and used to infect HL-60 cell line. The role of ALKBH5 in autophagy regulation was explored using RNA immunoprecipitation with next generation sequencing (RIP-Seq), m6A RNA Methylation Analysis, m6A immunocoprecipitation-quantitative polymerase chain reaction (MeRIP-qPCR) and Actinomycin D treatment. Results showed significantly reduced ALKBH5 levels in RA neutrophils compared to healthy controls (HC) and ankylosing spondylitis (AS) patients, correlating with RA disease activity. A novel predictive model incorporating ALKBH5, hemoglobin (HGB), and lymphocyte percentage (L%) exhibited enhanced efficacy in distinguishing RA patients from HC (AUC = 0.937) and AS patients (AUC = 0.943), and could reflect RA severity and activity. Additionally, autophagy levels in neutrophils were highest in RA synovial fluid, followed by RA peripheral blood, and lowest in HC peripheral blood, with ALKBH5 expression showing the opposite trend. Moreover, ALKBH5 negatively correlated with neutrophil autophagy and the silencing of ALKBH5 in HL-60 enhanced the autophagy. Silencing ALKBH5 increased m6A level of ATG7 mRNA and ATG7 mRNA stability. Mechanistically, ALKBH5 inhibited neutrophil autophagy through mediating m6A modification of the ATG7 mRNA. In conclusion, these findings demonstrate that ALKBH5 regulates neutrophil autophagy in RA, and the ALKBH5-HGB-L% model holds potential as a diagnostic and disease activity indicator for RA.
2025-08-22 | GSE305649 | GEO
Project description:Since m6A demethylases (FTO and ALKBH5) have been reported to be involved in pre-mRNA splicing regulation, we hypothesized that dynamic m6A distribution during mRNA maturation might involve removal of m6A in internal exons by FTO or ALKBH5 accompanied by splicing factors. To explore this we performed pull-down assays coupled with protein mass spectrometry.
2022-12-09 | PXD038705 | Pride
Project description:Oncogenic KRAS Mutations Confer a Unique Mechanotransduction Response to Peristalsis in Colorectal Cancer Cells
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