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

in The Journal of biological chemistry by Takuto Inoki, Akito Tsuruta, Yoshinori Masakado, Yuichiro Kai, Yuya Yoshida, Naoya Matsunaga, Shigehiro Ohdo, Satoru Koyanagi

TLDR

  • This study identified NAT10 as a key player in GBM tumorigenesis, linked its expression to poor prognosis, and revealed that targeting the NAT10-JARID2 axis may be a novel therapeutic approach for GBM treatment.

Abstract

Glioblastoma (GBM) is the most common and aggressive form of malignant brain cancer, with a poor prognosis and a five-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-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, 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.

Overview

  • The study aimed to investigate the role of N-acetyltransferase 10 (NAT10) in glioblastoma (GBM) tumorigenesis, its association with poor prognosis, and potential therapeutic targets.
  • The study used human GBM cell lines (U251 and A172) and xenograft mice to examine the effects of NAT10 on GBM stemness, tumor growth, and patient survival.
  • The primary objective was to identify the underlying molecular mechanisms by which NAT10 promotes GBM stemness and to explore potential therapeutic strategies to target this process.

Comparative Analysis & Findings

  • The study found that NAT10 expression is associated with poor prognosis in GBM patients, indicating its potential as a biomarker for GBM diagnosis and treatment.
  • NAT10 promotes GBM stemness by enhancing stemness properties in human GBM cell lines and contributing to the malignancy of GBM.
  • Knockdown of JARID2, a gene regulated by NAT10, significantly reduced GBM stemness, suppressed tumor growth, and extended the survival of xenograft mice, suggesting its potential as a therapeutic target.

Implications and Future Directions

  • The study suggests that targeting the NAT10-JARID2 axis may represent a novel therapeutic approach for the treatment of GBM, which warrants further investigation.
  • Future studies should aim to validate the translational potential of this axis in GBM patient samples and explore combination therapies that integrate NAT10 inhibition with other treatment modalities.
  • Elucidating the regulatory mechanisms governing NAT10-mediated gene expression will provide insights into the development of personalized treatment strategies for GBM patients.
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