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

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.

Zhang C ，Sun Q ，Zhang X ，Qin N ，Pu Z ，Gu Y ，Yan C ，Zhu M ，Dai J ，Wang C ，Li N ，Jin G ，Ma H ，Hu Z ，Zhang E ，Tan F ，Shen H ... -  《Cancer Communications》

KIAA1429 Induces m6A Modification of LINC01106 to Enhance the Malignancy of Lung Adenocarcinoma Cells via the JAK/STAT3 Pathway.

Xu D ，Wang Z ，Li F 《CRITICAL REVIEWS IN IMMUNOLOGY》

KIAA1429 promotes the progression of lung adenocarcinoma by regulating the m6A level of MUC3A.

Lung adenocarcinoma (LUAD) is one of the most frequently occurring human malignancies worldwide, but its potential molecular mechanism has not yet been fully elucidated. N6-methyladenosine (m6A), the most common internal chemical modification of mRNAs, is implicated in diverse pathological processes in different human malignancies, but its functions in LUAD remain elusive. The current study aimed to investigate the function and molecular mechanism of KIAA1429 in LUAD. The KIAA1429 expression level in LUAD tissues was assessed using databases and was detected in LUAD cells and tissues via quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot. m6A levels in LUAD tissues and cells were quantified. Next, correlation between the KIAA1429 expression level and the clinical and pathological features and prognosis of patients with LUAD was analyzed. Further, KIAA1429 levels were decreased, and LUAD cell proliferation, migration, invasion, and cycle were assessed. Prediction websites revealed the aberrant expression and probable methylation modification of MUC3A in LUAD, and correlation between MUC3A and KIAA1429 was analyzed. Ultimately, the impact of the KIAA1429 expression on MUC3A-mediated malignant phenotypes of LUAD was examined by a torsion test. KIAA1429 expression was remarkably high and m6A level was aberrantly elevated in LUAD cells and tissues. In addition, high KIAA1429 expression indicated a larger tumor diameter, higher tumor-node-metastasis stage, greater proneness to lymph node and distant metastasis, and lower overall survival rate. siRNA-triggered KIAA1429 downregulation dramatically suppressed LUAD cell proliferation, migration, invasion, and cell cycle arrest in the G1 phase. Bioinformatics analysis revealed that MUC3A was expressed in LUAD at an unusually high level and may be methylated under the control of KIAA1429. Western blot, qRT-PCR, and correlation analyses revealed a positive correlation between KIAA1429 expression level and MUC3A. Finally, torsion test results revealed that low KIAA1429 expression reversed LUAD cell migration, proliferation, and invasion facilitated by low MUC3A expression as well as cell cycle arrest in the G1 phase. KIAA1429 exhibited an unusually high expression in LUAD cells and tissues, and high KIAA1429 expression was correlated with the clinical and pathological features of patients with LUAD, thereby leading to an unsatisfactory prognosis. Furthermore, KIAA1429 regulates MUC3A expression through m6A modification to modulate LUAD cells to proliferate, migrate, invade, and induce cell cycle arrest.

Zhao W ，Xie Y 《-》

KIAA1429 regulates lung adenocarcinoma proliferation and metastasis through the PI3K/AKT pathway by modulating ARHGAP30 expression.

Alterations in epigenetic factors are recognized as key contributors to the emergence of human cancer. The active and reversible alteration of N6-methyladenosine (m6A) RNA is crucial for controlling gene activity and determining cellular destiny. Even with these insights, the triggering of KIAA1429 (also called VIRMA) and its role in lung adenocarcinoma (LUAD) is mostly unclear. As a result, the objective of this study was to elucidate how KIAA1429 contributes to cancer development in LUAD. This study utilized multiple methods for investigation, encompassing the in vitro functional examination of KIAA1429 in lung adenocarcinoma cells, transcriptome sequencing, methylation RNA immunoprecipitation sequencing (MeRIP-seq), as well as RNA stability tests to ascertain the half-life and stability of the target genes. The results indicated that modifying the expression of KIAA1429 regulated the proliferation and metastasis of LUAD. By employing transcriptome sequencing alongside MeRIP-seq analysis, the research pinpointed genes affected by m6A alterations triggered by KIAA1429. In a more detailed manner, it was discovered that KIAA1429 plays a regulatory role in the expression of ARHGAP30. Suppressing KIAA1429 results in reduced m6A levels in the mRNA of the target gene ARHGAP30, boosting its stability and expression, thus inhibiting tumor proliferation and metastasis. This study revealed the activation mechanism and pivotal function of KIAA1429 in LUAD tumor development, paving the way for molecular-based interventions for LUAD.

Guo W ，Wang T ，Huai Q ，Guo L ，Wang X ，He J ... -  《-》

KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo-YAP pathway.

N6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the progression of diffuse large B-cell lymphoma (DLBCL) remains undefined. The expression and clinical significance of KIAA1429 were verified by our clinical data. CRISPR/Cas9 mediated KIAA1429 deletion, and CRISPR/dCas9-VP64 for activating endogenous KIAA1429 was used to evaluate its biological function. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to investigate the regulatory mechanism of KIAA1429 in DLBCL. Tumor xenograft models were established for in vivo experiments. Dysregulated expression of m6A regulators was observed, and a novel predictive model based on m6A score was established in DLBCL. Additionally, elevated KIAA1429 expression was associated with poor prognosis of patients with DLBCL. Knockout of KIAA1429 repressed DLBCL cell proliferation, facilitated cell cycle arrest in the G2/M phase, induced apoptosis in vitro, and inhibited tumor growth in vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) was identified as a downstream target of KIAA1429, which mediated m6A modification of CHST11 mRNA and then recruited YTHDF2 for reducing CHST11 stability and expression. Inhibition of CHST11 diminished MOB1B expression, resulting in inactivation of Hippo-YAP signaling, reprogramming the expression of Hippo target genes. Our results revealed a new mechanism by which the Hippo-YAP pathway in DLBCL is inactivated by KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression.

Chen X ，Lu T ，Cai Y ，Han Y ，Ding M ，Chu Y ，Zhou X ，Wang X ... -  《-》