Department of Epidemiology, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, P. R. China.
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China.
Cancer Commun (Lond). 2022 Jul;42(7):609-626. doi: 10.1002/cac2.12325. Epub 2022 Jun 21.
Epigenetic alterations have been shown to contribute immensely to human carcinogenesis. Dynamic and reversible N6-methyladenosine (m6A) RNA modification regulates gene expression and cell fate. However, the reasons for activation of KIAA1429 (also known as VIRMA, an RNA methyltransferase) and its underlying mechanism in lung adenocarcinoma (LUAD) remain largely unexplored. In this study, we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.
Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase. The in vitro and in vivo functions of KIAA1429 were investigated. Transcriptome sequencing, methylated RNA immunoprecipitation sequencing (MeRIP-seq), m6A dot blot assays and RNA immunoprecipitation (RIP) were performed to confirm the modified gene mediated by KIAA1429. RNA stability assays were used to detect the half-life of the target gene.
Copy number amplification drove higher expression of KIAA1429 in LUAD, which was correlated with poor overall survival. Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD. Mechanistically, the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays. We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner. Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA, leading to enhanced YTH m6A RNA binding protein 2 (YTHDF2, the m6A "reader")-dependent BTG2 mRNA stability and promoted the expression of BTG2; thus, participating in the tumorigenesis of LUAD.
Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis, which may provide a novel view on the targeted molecular therapy of LUAD.
表观遗传改变已被证明对人类癌症发生有巨大贡献。动态和可逆的 N6-甲基腺苷（m6A）RNA 修饰调节基因表达和细胞命运。然而，KIAA1429（也称为 VIRMA，一种 RNA 甲基转移酶）的激活原因及其在肺腺癌（LUAD）中的潜在机制在很大程度上仍未得到探索。在这项研究中，我们旨在阐明 KIAA1429 在 LUAD 肿瘤发生中的致癌作用。
使用 LUAD 数据的全基因组测序和转录组测序分析 RNA 甲基转移酶的基因扩增。研究了 KIAA1429 的体外和体内功能。进行了转录组测序、甲基化 RNA 免疫沉淀测序（MeRIP-seq）、m6A 点印迹测定和 RNA 免疫沉淀（RIP）实验以确认由 KIAA1429 介导的修饰基因。使用 RNA 稳定性测定来检测靶基因的半衰期。
拷贝数扩增驱动 LUAD 中 KIAA1429 的高表达，与整体生存不良相关。操纵 KIAA1429 的表达可以调节 LUAD 的增殖和转移。从机制上讲，通过转录组测序和 MeRIP-seq 测定证实了 KIAA1429 介导的 m6A 修饰的靶基因。我们还揭示了 KIAA1429 可以以 m6A 依赖的方式调节 BTG2 的表达。敲低 KIAA1429 显著降低了 BTG2 mRNA 的 m6A 水平，导致增强了 YTH m6A RNA 结合蛋白 2（YTHDF2，m6A“读取器”）依赖性 BTG2 mRNA 稳定性，并促进了 BTG2 的表达；从而参与 LUAD 的肿瘤发生。
我们的数据揭示了 KIAA1429 在 LUAD 肿瘤发生中的激活机制和重要作用，这可能为 LUAD 的靶向分子治疗提供新的视角。
