KEY TAKEAWAYS
- The study aimed to investigate NAT10’s role and mechanisms in DLBCL using clinical samples and various assays.
- The results showed the essential role of ac4C RNA modification mediated by NAT10 in DLBCL and provided insights into novel epigenetic-based therapeutic strategies.
Studies have indicated that posttranscriptional modifications play a crucial role in the tumorigenesis of diffuse large B-cell lymphoma (DLBCL). N4-acetylcytidine (ac4C) modification, catalyzed by N-acetyltransferase 10 (NAT10), is a novel chemical modification that enhances translation efficiency and mRNA stability.
Mengfei Ding and the team aimed to investigate NAT10’s role and mechanisms in DLBCL using clinical samples and advanced molecular assays.
Researchers utilized GEO databases and clinical samples to examine the expression and clinical significance of NAT10 in DLBCL. They conducted a CRISPR/Cas9-mediated knockout of NAT10 to determine its biological functions in DLBCL.
To explore the mechanisms by which NAT10 contributes to DLBCL progression, they performed RNA sequencing, acetylated RNA immunoprecipitation sequencing (acRIP-seq), LC-MS/MS, RNA immunoprecipitation (RIP)-qPCR, and RNA stability assays.
The study demonstrated that NAT10-mediated ac4C modification regulates the occurrence and progression of DLBCL. Dysregulated expression of N-acetyltransferases was observed in DLBCL samples, with high NAT10 expression linked to poor prognosis in patients with DLBCL. NAT10 deletion inhibited cell proliferation and induced G0/G1 phase arrest.
Additionally, NAT10 knockout increased DLBCL cell sensitivity to ibrutinib. AcRIP-seq identified solute carrier family 30 member 9 (SLC30A9) as a downstream target of NAT10 in DLBCL. NAT10 regulated the mRNA stability of SLC30A9 in an ac4C-dependent manner. Genetic silencing of SLC30A9 suppressed DLBCL cell growth by regulating the activation of the AMP-activated protein kinase (AMPK) pathway.
The study concluded that ac4C RNA modification mediated by NAT10 plays an essential role in DLBCL, providing insights into novel epigenetic-based therapeutic strategies.
Funidng was provided by the National Natural Science Foundation, Key Research and Development Program of Shandong Province,China Postdoctoral Science Foundation,Translational Research Grant of NCRCH, Shandong Provincial Natural Science Foundation,Taishan Scholars Program of Shandong Province, Shandong Provincial Engineering Research Center of Lymphoma, and Academic Promotion Programme of Shandong First Medical University.
Source: https://pubmed.ncbi.nlm.nih.gov/38961519/
Ding M, Yu Z, Lu T, et al. (2024). “N-acetyltransferase 10 facilitates tumorigenesis of diffuse large B-cell lymphoma by regulating AMPK/mTOR signalling through N4-acetylcytidine modification of SLC30A9.” Clin Transl Med. 2024;14(7):e1747. doi:10.1002/ctm2.1747
