LncRNA LINC00969 promotes acquired gefitinib resistance by epigenetically suppressing of NLRP3 at transcriptional and posttranscriptional levels to inhibit pyroptosis in lung cancer

Abstract

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment prolongs the survival of lung cancer patients harbouring activating EGFR mutations. However, resistance to EGFR-TKIs is inevitable after long-term treatment. Molecular mechanistic research is of great importance in combatting resistance. A comprehensive investigation of the molecular mechanisms underlying resistance has important implications for overcoming resistance. An accumulating body of evidence shows that lncRNAs can contribute to tumorigenesis and treatment resistance. By bioinformatics analysis, we found that LINC00969 expression was elevated in lung cancer cells with acquired gefitinib resistance. LINC00969 regulated resistance to gefitinib in vitro and in vivo. Mechanistically, gain of H3K4me1 and H3K27Ac led to the activation of LINC00969 expression. LINC00969 interacts with EZH2 and METTL3, transcriptionally regulates the level of H3K27me3 in the NLRP3 promoter region, and posttranscriptionally modifies the m6A level of NLRP3 in an m6A-YTHDF2-dependent manner, thus epigenetically repressing NLRP3 expression to suppress the activation of the NLRP3/caspase-1/GSDMD-related classical pyroptosis signalling pathways, thereby endowing an antipyroptotic phenotype and promoting TKI resistance in lung cancer. Our findings provide a new mechanism for lncRNA-mediated TKI resistance from the new perspective of pyroptosis via simultaneous regulation of histone methylation and RNA methylation. The pivotal role of LINC00969 gives it the potential to be a novel biomarker and therapeutic target for overcoming EGFR-TKI resistance in lung cancer.

Harnessing innate immune pathways for therapeutic advancement in cancer

“… 460 , 461 The suppression of NLRP3 can lead to resistance in NSCLC to the drug gefitinib, an EGFR inhibitor. 462 Secondly, the activation of the NLR pathway reshapes the immune microenvironment through the secretion of pro-inflammation cytokines such as IL-1 and IL-18. 463 The IL-1 induced by NLRP3 inflammasomes could activate the DCs and enhance their cross-priming ability, while IL-18 participates in tumor suppression by inducing the production and activation of the tumor suppressors IFN-γ and STAT1.…”

Epigenetic regulation of diverse cell death modalities in cancer: a focus on pyroptosis, ferroptosis, cuproptosis, and disulfidptosis

“…m6A modification can also regulate pyroptosis. Interestingly, up-regulation of H3K4me1 and H3K27Ac promotes lncRNA LINC00969 expression in NSCLC cells, then LINC00969 interacts with METTL3 and inhibits NLRP3 in an m6A-YTHDF2-dependent manner to inhibit pyroptosis in NSCLC, thereby promoting drug resistance of NSCLC [ 85 ]. Tanshinone IIA enhances pyroptosis and inhibits HK1 cell proliferation by regulating miR-125b/foxp3/caspase-1/GSDMD signaling, providing strong evidence for the treatment of nasopharyngeal carcinoma [ 86 ].…”

New insights into the interaction between m6A modification and lncRNA in cancer drug resistance

“…Consequently, the repression of NLRP3 resulted to gefitinib resistance in NSCLC through the suppression of the classical pyroptosis signalling pathway. 109 Similarly, the expression of lncRNA SNHG17 was increased in gefitinib‐resistant lung cancer cells and contributed to the development of gefitinib resistance in LUAD. Mechanistically, METTL3‐mediated m6A modification enhanced the stability of SNHG17, leading to an upregulation in its expression.…”