1. Academic Validation
  2. Depletion of the N6-Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4

Depletion of the N6-Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4

  • Cell Death Dis. 2024 Mar 1;15(3):181. doi: 10.1038/s41419-024-06486-z.
Limei Deng 1 2 Yunbo Di 1 Caiyun Chen 1 Juan Xia 3 Bingxi Lei 4 Ning Li 5 6 Qingyu Zhang 7
Affiliations

Affiliations

  • 1 Laboratory of Obstetrics and Gynecology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001, China.
  • 2 The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, 524023, China.
  • 3 Department of Hematology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001, China.
  • 4 Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. leibingxi@mail.sysu.edu.cn.
  • 5 The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, 524023, China. lining.201@163.com.
  • 6 Department of Hematology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001, China. lining.201@163.com.
  • 7 Laboratory of Obstetrics and Gynecology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001, China. zqy0401@163.com.
Abstract

Emerging evidence highlights the multifaceted contributions of m6A modifications to glioma. IGF2BP3, a m6A modification reader protein, plays a crucial role in post-transcriptional gene regulation. Though several studies have identified IGF2BP3 as a poor prognostic marker in glioma, the underlying mechanism remains unclear. In this study, we demonstrated that IGF2BP3 knockdown is detrimental to cell growth and survival in glioma cells. Notably, we discovered that IGF2BP3 regulated Ferroptosis by modulating the protein expression level of GPX4 through direct binding to a specific motif on GPX4 mRNA. Strikingly, the m6A modification at this motif was found to be critical for GPX4 mRNA stability and translation. Furthermore, IGF2BP3 knockdown glioma cells were incapable of forming tumors in a mouse xenograft model and were more susceptible to phagocytosis by microglia. Our findings shed LIGHT on an unrecognized regulatory function of IGF2BP3 in Ferroptosis. The identification of a critical m6A site within the GPX4 transcript elucidates the significance of post-transcriptional control in Ferroptosis.

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