2. Academic Validation
  3. The N6-methyladenosine writer METTL3 promotes breast cancer progression through YTHDF2-dependent posttranscriptional silencing of GSDMD

The N6-methyladenosine writer METTL3 promotes breast cancer progression through YTHDF2-dependent posttranscriptional silencing of GSDMD

  • Apoptosis. 2025 Feb;30(1-2):226-238. doi: 10.1007/s10495-024-02037-1.
You Shuai # 1,  Zhonghua Ma # 2,  Jie Ju # 3,  Chunxiao Li 1,  Xiaorong Bai 4,  Jian Yue 5,  Xue Wang 5,  Peng Yuan 6,  Haili Qian 7
Affiliations

Affiliations

  • 1 Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
  • 2 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Endoscopy, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
  • 3 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Day Care, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
  • 4 Department of Breast Surgery, GanSu Provincial Cancer Hospital, Lanzhou, 730050, China.
  • 5 Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
  • 6 Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. yuanpengyp01@163.com.
  • 7 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. qianhaili001@163.com.
  • # Contributed equally.
PMID: 39627574 DOI: 10.1007/s10495-024-02037-1
Abstract

Cell Pyroptosis is a form of programmed cell death, with Gasdermin-D (GSDMD) acting as its key executor. While activating Pyroptosis represents a promising therapeutic strategy for Cancer, the regulatory mechanisms governing GSDMD expression during cell death remain poorly understood. In this study, we identified METTL3 as a negative regulator of GSDMD-mediated Pyroptosis, with high expression in breast Cancer (BC) cells. YTHDF2 was found to recognize the m6A modification of GSDMD, thereby decreasing its stability. Finally, in vivo experiments further demonstrated the inhibitory effect of the METTL3 Inhibitor STM2457 on tumors. Overall, these findings suggest that inhibition of METTL3 can enhance GSDMD-mediated Pyroptosis and reveal a novel regulatory mechanism governing GSDMD expression, presenting a novel strategy for Cancer treatment.

Keywords

GSDMD; METTL3; N6-methyladenosine; Pyroptosis; YTHDF2.

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