NAT10 REGULATES THE AMPK SIGNALING PATHWAY TO PROMOTE DLBCL PROGRESSION VIA AC4C ACETYLATION OF SLC30A9 MRNA

Abstract

Introduction: N-acetyltransferase 10 (NAT10) is the only confirmed regulator to mediate the N4-acetylcytidine (ac4C) modification of mRNA and is crucial for mRNA stability and translation efficiency. However, its role in diffuse large B-cell lymphoma (DLBCL) development and prognosis has not yet been explored. Herein, we explored the functional significance and regulatory mechanism of NAT10 mediated mRNA ac4C modification in DLBCL, which is expected to propose novel therapeutic strategy. Methods: The expression levels of NAT10 were evaluated in DLBCL cell lines and lymph node biopsies tissues, and its prognostic value in patients was further analyzed. Stable NAT10 knockout DLBCL cell lines were constructed using CRISPR/Cas9 mediated genomic deletion. The biological functions of NAT10 in DLBCL cells were analyzed in vitro by cell proliferation and cell cycle assays. Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis of DLBCL cells in vivo. RNA sequencing, acetylated RNA immunoprecipitation sequencing (acRIP-seq), LC-MS/MS, RIP and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in DLBCL progression. Results: NAT10 was upregulated in DLBCL cell lines and tissues. NAT10 high expression was associated with poor patient prognosis. Knockout of NAT10 impaired cellular phase progression and proliferation of DLBCL. Further analysis revealed that NAT10-mediated ac4C acetylation of SLC30A9 transcript and subsequently stabilized SLC30A9 mRNA, leading to activation of AMPK signaling and thereby facilitating DLBCL progression (Figure 1). Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, genomics, epigenomics, and other -omics No conflicts of interests pertinent to the abstract.