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

Zhang, Chang; Sun, Qi; Zhang, Xu; Qin, Na; Pu, Zhening; Gu, Yayun; Yan, Caiwang; Zhu, Meng; Dai, Juncheng; Wang, Cheng; Li, Ni; Jin, Guangfu; Ma, Hongxia; Hu, Zhibin; Zhang, Erbao; Tan, Fengwei; Shen, Hongbing

doi:10.1002/cac2.12325

Cited by 27 publications

(9 citation statements)

References 52 publications

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“…Various m6A“reader” proteins, including YTHDF1, YTHDF2 and YTHDF3, can recognize m6A-modified sites and exploit them for different functions. In particular, YTHDF2 can regulate cancer progression by binding to m6A-modified sites to mediate mRNA degradation [ 45 , 50 ]. Moreover, our analysis revealed a positive expression correlation between LINC00969 and YTHDF2 expression in gefitinib-resistant tissues (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Dai

Yin

et al. 2023

Cell Death Dis

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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.

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Section: Resultsmentioning

confidence: 99%

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

Dai

Yin

et al. 2023

Cell Death Dis

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“…Furthermore, YTHDF2 produces a positive effect on lung adenocarcinoma progression through the mRNA decay of AXIN1, a negative regulator of the WNT/β-catenin pathway ( 235 ). YTHDF2 produces the same effect in a VIRMA-m 6 A-dependent fashion in lung adenocarcinoma and NSCLC by reducing BTG2 mRNA and DAPK3 mRNA stability, respectively ( 236 , 237 ). Nevertheless, YTHDF2 induces sensitivity of lung adenocarcinoma to gefitinib via cleavage of circASK1 ( 238 ).…”

Section: The Role Of the Ythdf Family In Cancersmentioning

confidence: 99%

N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms

Chen

Gao

et al. 2023

Front. Immunol.

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As the most abundant and conserved internal modification in eukaryote RNAs, N6-methyladenosine (m6A) is involved in a wide range of physiological and pathological processes. The YT521-B homology (YTH) domain-containing family proteins (YTHDFs), including YTHDF1, YTHDF2, and YTHDF3, are a class of cytoplasmic m6A-binding proteins defined by the vertebrate YTH domain, and exert extensive functions in regulating RNA destiny. Distinct expression patterns of the YTHDF family in specific cell types or developmental stages result in prominent differences in multiple biological processes, such as embryonic development, stem cell fate, fat metabolism, neuromodulation, cardiovascular effect, infection, immunity, and tumorigenesis. The YTHDF family mediates tumor proliferation, metastasis, metabolism, drug resistance, and immunity, and possesses the potential of predictive and therapeutic biomarkers. Here, we mainly summary the structures, roles, and mechanisms of the YTHDF family in physiological and pathological processes, especially in multiple cancers, as well as their current limitations and future considerations. This will provide novel angles for deciphering m6A regulation in a biological system.

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“…KIAA1429 is an m6A methyltransferase that connects the catalytic (core) part and the RNA substrate in the methyltransferase complex, thereby guiding m6A installation at specified locations 18 . Moreover, KIAA1429 is upregulated in numerous cancers, such as liver cancer, 19 B‐cell lymphoma18, and lung adenocarcinoma 20 . KIAA1429 is known to produce tumorigenic activity by regulating different targets (ID2, DAPK3, GATA3) and boosting the malignant features of tumors by changing m6A modification21.…”

Section: Introductionmentioning

confidence: 99%

Inhibin A contributes to the tumorigenesis of oral squamous cell carcinoma by KIAA1429‐mediated m6A modification

Chen,

Fan

2024

J Oral Pathology Medicine

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BackgroundInhibin A and N6‐methyladenosine methylation modifications participate in oral squamous cell carcinoma development. However, the N6‐methyladenosine modification of Inhibin A in oral squamous cell carcinoma has not been revealed. This study reveals a key gene “Inhibin A” that may affect the tumorigenesis of oral squamous cell carcinoma and its molecular mechanisms on N6‐methyladenosine methyltransferase KIAA1429‐mediated N6‐methyladenosine methylation modification.MethodsBioinformatics analysis and quantitative real‐time polymerase chain reaction identified the potential regulatory genes in oral squamous cell carcinoma. We examined the changes in the proliferation (Cell Counting Kit‐8 assay), migration (transwell migration assay), and invasion (transwell invasion assays) of oral squamous cell carcinoma cells. We performed a xenograft tumor experiment to validate the role of Inhibin A in oral squamous cell carcinoma in vivo. The interactions between Inhibin A and KIAA1429 were analyzed using bioinformatics, methylated RNA immunoprecipitation‐qPCR, quantitative real‐time polymerase chain reaction, and Western blotting experiments.ResultsInhibin A had the highest expression in patients with oral squamous cell carcinoma. Inhibin A silencing impaired the ability of oral squamous cell carcinoma cells to proliferate, migrate, and invade, as well as limited the tumorous growth of oral squamous cell carcinoma cells in vivo. Bioinformatics analysis showed that Inhibin A expression positively interacted with KIAA1429 expression in The Cancer Genome Atlas database. The levels were also upregulated in our clinical samples. Furthermore, KIAA1429 silencing repressed the N6‐methyladenosine level of Inhibin A in oral squamous cell carcinoma.ConclusionsInhibin A promotes the tumorigenesis of oral squamous cell carcinoma by KIAA1429‐mediated N6‐methyladenosine modification. This study adds to our current knowledge of the molecular mechanisms underlying oral squamous cell carcinoma malignancy.

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

Abstract: Background: Epigenetic alterations have been shown to contribute immensely to human carcinogenesis. Dynamic and reversible N6-methyladenosine (m6A)

Cited by 27 publications

References 52 publications

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

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

N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms

Inhibin A contributes to the tumorigenesis of oral squamous cell carcinoma by KIAA1429‐mediated m6A modification

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