METTL3 regulates FAM83D m6A modification to accelerate tumorigenesis of triple-negative breast cancer via the Wnt/β-catenin pathway

Abstract

N6-methyladenosine (m⁶A) modification, the most abundant methylation modification on eukaryotic mRNAs, was implicated in the tumourigenesis. This study aimed to explore the role of methyltransferase like 3 (METTL3) in triple-negative breast cancer progression and its underlying mechanisms. FAM83D was markedly elevated in triple-negative breast cancer tissues and cells, and high expression of FAM83D was related to the poor prognosis of triple-negative breast cancer patients. FAM83D knockdown significantly retarded cell proliferation, invasion, stemness, and accelerated cell apoptosis in triple-negative breast cancer cells. On the contrary, overexpression of FAM83D promoted the malignant behaviors. METTL3 could interact with FAM83D and mediate m⁶A modification of FAM838D. Moreover, METTL3 positively regulated FAM83D expression, and FAM83D overexpression could block the inhibition effects of MRTTL3 knockdown on the malignant behaviors. METTL3 knockdown decreased FAM83D expression to inhibit the Wnt/β-catenin pathway. In addition, knockdown of FAM83D also showed the repressive effects on tumor growth in triple-negative breast cancer in vivo. These findings suggested that METTL3 could modulate FAM83D protein expression through m⁶A modification to aggravate triple-negative breast cancer progression via the Wnt/β-catenin pathway.

Keywords: FAM83D; METTL3; N6-methyladenosine; Triple-negative breast cancer; Wnt/β-catenin pathway.