KIAA1429 REGULATES HIPPO‐YAP PATHWAY TO MAINTAIN THE TUMORIGENICITY OF DIFFUSE LARGE B‐CELL LYMPHOMA VIA AN M6A‐DEPENDENT MANNER

Abstract

Introduction: N6-methyladenosine (m6A) is the most abundant form of chemical modification in eukaryotes. m6A methylation is dynamically modulated by diverse types of regulators, including methyltransferases (‘writers’), RNA binding proteins (‘readers’), and demethylases (‘erasers’). Growing evidence has shown that m6A methylation plays an essential role in the development and progression of multiple cancers. However, the functions of m6A methyltransferase KIAA1429 in diffuse large B-cell lymphoma (DLBCL) remain undefined. Here, we aimed to unravel an epitranscriptomic mechanism mediated by the m6A methyltransferase KIAA1429 in DLBCL. Methods: Collecting lymph node biopsy samples from 60 de novo DLBCL patients and 20 reactive hyperplasia cases after informed consent. The biological function of KIAA1429 was evaluated using CRISPR/Cas9 mediated genomic deletion and CRISPR/dCas9-VP64 activation. RNA-seq, MeRIP-seq, RIP assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to explore the regulatory mechanism of KIAA1429 in DLBCL. DLBCL cells were subcutaneously injected into SCID-Beige mice to establish xenograft models. The Institutional Animal Care guidelines were followed during the animal experiments. Results: m6A regulators were dysregulated in DLBCL, and a predictive model based on m6A score was developed. KIAA1429 expression was found to be elevated and associated with poor prognosis. KIAA1429 knockout inhibited DLBCL cell proliferation, induced cell cycle arrest in the G2/M phase, promoted apoptosis in vitro, and repressed tumor growth in vivo. Furthermore, KIAA1429 mediated m6A modification of CHST11 mRNA and recruited YTHDF2 to reduce the stability and expression of CHST11. By decreasing MOB1B expression, CHST11 inhibited Hippo-YAP signaling, reprogramming the expression of Hippo target genes (Figure 1). Conclusions: In summary, we identified for the first time that m6A methylation regulators were dysregulated, and its risk score could exert as an independent prognostic indicator in DLBCL. More importantly, our study identified a novel mechanism in which KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11 inactivates the Hippo-YAP pathway in DLBCL, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression. Keywords: aggressive B-cell non-Hodgkin lymphoma, bioinformatics, computational and systems biology, genomics, epigenomics, and other -omics No conflicts of interests pertinent to the abstract.