N6-methyladenosine (m6A) methyltransferase KIAA1429 accelerates the gefitinib resistance of non-small-cell lung cancer

Abstract

N6-methyladenosine (m6A) modification has been convincingly identified to be a critical regulator in human cancer. However, the contribution of m6A to NSCLC gefitinib resistance is still largely unknown. Here, we screened and identified that m6A methyltransferase KIAA1429 was highly expressed in gefitinib-resistant NSCLC cells (PC9-GR), tissues, and closely related to unfavorable survival. Functionally, KIAA1429 accelerated the gefitinib resistance of NSCLC in vitro. Depletion of KIAA1429 repressed the tumor growth of PC9-GR cells in vivo. Mechanistically, KIAA1429 enhanced the mRNA stability of HOXA1 through targeting its 3′-untranslated regions (3′-UTR). Overall, our findings indicate that KIAA1429 plays essential oncogenic roles in NSCLC gefitinib resistance, which may provide a feasible therapeutic target for NSCLC.

Gene amplification‐driven RNA methyltransferase KIAA1429 promotes tumorigenesis by regulating BTG2 via m6A‐YTHDF2‐dependent in lung adenocarcinoma

“…KIAA1429 mediates preferential mRNA methylation in the 3’UTR and near the stop codon [37]. Previous studies have shown that KIAA1429 could play an essential role in tumorigenesis, including lung cancer [38–40]. For instance, KIAA1429 promotes the migration and invasion of HCC by inhibiting ID2 via upregulating m6A modification of ID2 mRNA [38].…”

“…*P < 0.05, **P < 0.01. Abbreviations: IGV, Integrative Genomics Viewer; IP, immunoprecipitation; m6A, N6-methyladenosine; 3'UTR, 3'untranslated region; MeRIP-qPCR, methylated RNA immunoprecipitation -qPCR; TCGA, The Cancer Genome Atlas; LUAD, lung adenocarcinoma; qRT-PCR, quantitative real-time polymerase chain reaction; RIP, RNA immunoprecipitation; IgG, immunoglobin G. studies have shown that KIAA1429 could play an essential role in tumorigenesis, including lung cancer [38][39][40]. For instance, KIAA1429 promotes the migration and invasion of HCC by inhibiting ID2 via upregulating m6A modification of ID2 mRNA [38].…”

“…KIAA1429 regulates the expression of MUC3A by modifying m6A, thus regulating the proliferation and migration of LUAD cells [39]. KIAA1429 can accelerate the gefitinib resistance of NSCLC by targeting HOXA1 3'UTR to enhance its mRNA stability [40]. However, the reason for the activation of KIAA1429 remains unclear.…”

m6A Modification: A Double-Edged Sword in Tumor Development

“…They found that by modifying METTL3 with small ubiquitin-like modifier 1 (SUMO1), the m6A level was reduced on mRNAs, which eventually contributed to the progression of NSCLC (84). Tang et al identified that KIAA1429 accelerated the gefitinib resistance of NSCLC in vitro and in vivo by enhancing the stability of HOXA1 mRNA in an m6A-dependent manner (60). Notably, these studies demonstrate that METTL3 may act in a tumorigenesis role in lung cancer via not only target mRNA and miRNA but also by being modified by other genes.…”

“…Tang et al. identified that KIAA1429 accelerated the gefitinib resistance of NSCLC in vitro and in vivo by enhancing the stability of HOXA1 mRNA in an m6A-dependent manner ( 60 ). Notably, these studies demonstrate that METTL3 may act in a tumorigenesis role in lung cancer via not only target mRNA and miRNA but also by being modified by other genes.…”