METTL3 stabilizes FASN mRNA by mediating mA modification to promote malignant progression of diffuse large B-cell lymphoma.

[BACKGROUND] Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma. Fatty acid synthase (FASN) is a key lipogenic enzyme implicated in tumor progression, but its regulation in DLBCL is poorly understood.

[METHODS] The function of FASN in DLBCL was explored using database analysis, clinical sample analysis, and cellular phenotyping experiments. Candidate mA sites on FASN mRNA were predicted using the SRAMP database. Bioinformatics analyses and experimental techniques were conducted to elucidate the role of methyltransferase-like 3 (METTL3) on cell phenotypes and its regulation of FASN. The findings were further confirmed in mice models and clinical sample analyses.

[RESULTS] FASN was highly expressed in DLBCL and positively correlated with poor prognosis. FASN knockdown inhibited the malignant phenotypes in DLBCL cells by suppressing the PI3K/AKT and MAPK/ERK signaling pathways, as well as promoting endoplasmic reticulum (ER) stress. The analysis of FASN mRNA revealed the presence of mA modification sites, and a positive correlation was identified between METTL3 and FASN. The impact of METTL3 knockdown on the malignant phenotypes of DLBCL cells was consistent with the effects induced by FASN knockdown, whereas METTL3 overexpression reversed the effects of FASN knockdown. Mechanistically, METTL3 stabilized FASN expression by mediating mA modification of FASN mRNA, thereby facilitating DLBCL progression.

[CONCLUSION] METTL3 stabilizes FASN expression through mA modification, thereby facilitating the DLBCL progression by activating the PI3K/AKT and MAPK/ERK signaling pathways and inhibiting the ER stress response pathway. The METTL3/FASN axis represents a potential therapeutic target, especially in METTL3/FASN-high DLBCL subgroups.