NAT10 Modulates Breast Cancer Progression Via Ac⁴C-Mediated Regulation of TRAF6 Expression and Glycolytic Metabolism.

Abstract

NAT10, an essential enzyme catalyzing RNA ac⁴C modification, is recognized as a critical regulator of tumorigenesis and progression. This study investigates the role and underlying molecular mechanisms of NAT10 in breast cancer. We found that NAT10 is significantly overexpressed in breast cancer tissues compared to adjacent normal tissues, exhibiting high diagnostic accuracy (AUC = 0.9702, p < 0.001). Consistently, NAT10 expression was also elevated in breast cancer cell lines. Knockdown of NAT10 potently inhibited cell viability, glycolysis (as indicated by reduced glucose uptake, lactate production, and ECAR), and metastatic potential (manifested as suppressed migration and invasion) in breast cancer cells. Mechanistically, NAT10 regulated TRAF6 expression and stability through ac⁴C modification; NAT10 knockdown led to reduced ac⁴C enrichment on TRAF6 mRNA and accelerated its degradation. Rescue experiments confirmed that TRAF6 overexpression partially reversed the inhibitory effects of NAT10 knockdown on glycolysis and metastasis. In vivo, NAT10 knockdown significantly suppressed tumor growth in nude mice, which was associated with reduced expression of Ki67 and TRAF6 in tumor tissues. Collectively, our findings highlight NAT10 as a key regulator of breast cancer progression via ac⁴C-mediated TRAF6 modulation, suggesting it as a promising therapeutic target for breast cancer therapy.