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

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

A new perspective on hematological malignancies: m6A modification in immune microenvironment

“…The elevated expression of this enzyme is associated with poor clinical outcomes. Mechanistically, KIAA1429 promotes the progression of DLBCL by inhibiting CHST11 expression and attenuating the activation of Hippo-YAP signaling induced by the interaction of CHST11 with the oncogene MOB1B ( 73 ).…”

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

“…m6A is the most common among various eukaryotic mRNA epigenetic modifications 17 . 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 .…”

m6A modification of AC026356.1 facilitates hepatocellular carcinoma progression by regulating the IGF2BP1-IL11 axis

“…Increasing evidences have shown that m 6 A modification plays critical roles in RNA fate and function, such as RNA splicing, export, stability, and translation 16 – 19 . Thus, through regulating RNA fate, m 6 A modification participates in various physiopathological processes 20 – 22 . Consistently, m 6 A modification of different mRNAs show diverse roles in malignancies, including HCC 23 , 24 .…”