N-acetyltransferase 10 promotes glioblastoma malignancy via mRNA stabilization of jumonji and AT-rich interaction domain containing 2.

Glioblastoma (GBM) is the most common and aggressive form of malignant brain cancer, with a poor prognosis and a 5-year survival rate of approximately 15%. The malignancy of GBM, including its treatment resistance and high recurrence rate, is largely attributed to the presence of cancer stem cells. Recent studies have identified the N-acetyltransferase 10 (NAT10), an enzyme responsible for catalyzing N(4)-acetylcytidine (ac4C) modification in RNA, as a key factor in cancer biology, with diverse roles across multiple cancer types. However, the specific contribution of this RNA modification to the malignancy of GBM remains unexplored. Here, we demonstrate that NAT10 expression is associated with poor prognosis in GBM patients and that NAT10 promotes GBM malignancy by enhancing stemness properties in human GBM cell line U251 and A172. A search for the underlying mechanism of NAT10-mediated enhancement of GBM stemness led to identification of polycomb repressive complex 2 (PRC2)-related genes as an epigenetic regulator. NAT10 mediates the acetylation of the coding region of Jumonji and AT-rich Interaction Domain containing 2 (JARID2) mRNA, which results in increased mRNA stability and elevated protein levels. Notably, the knockdown of JARID2 significantly reduced GBM stemness, suppressed tumor growth, and extended the survival of xenograft mice. Our findings suggest that NAT10-mediated acetylation of JARID2 mRNA up-regulates its protein levels, thereby promoting stemness and contributing to the malignancy of GBM. Targeting this NAT10-JARID2 axis may represent a novel therapeutic approach for treatment of GBM.