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  3. HDAC2-Mediated METTL3 Delactylation Promotes DNA Damage Repair and Chemotherapy Resistance in Triple-Negative Breast Cancer

HDAC2-Mediated METTL3 Delactylation Promotes DNA Damage Repair and Chemotherapy Resistance in Triple-Negative Breast Cancer

  • Adv Sci (Weinh). 2025 Feb 14:e2413121. doi: 10.1002/advs.202413121.
Xiaoniu He 1,  Yuanpei Li 2,  Jian Li 3,  Yu Li 4,  Sijie Chen 4,  Xia Yan 1,  Zhangrong Xie 4,  Jiangfeng Du 5,  Guoan Chen 4,  Jianbo Song 1,  Qi Mei 6
Affiliations

Affiliations

  • 1 Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, China.
  • 2 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 3 Institute of Molecular Medicine and Experimental Immunology, University Clinic of Rheinische Friedrich-Wilhelms-University, 53127, Bonn, Germany.
  • 4 Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.
  • 5 Department of Medical Imaging, Shanxi Key Laboratory of Intelligent Imaging and Nanomedicine, First Hospital of Shanxi Medical University, Taiyuan, 030001, China.
  • 6 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
PMID: 39950833 DOI: 10.1002/advs.202413121
Abstract

The current treatment of triple-negative breast Cancer (TNBC) is still primarily based on platinum-based chemotherapy. However, TNBC cells frequently develop resistance to platinum and experience relapse after drug withdrawal. It is crucial to specifically target and eliminate cisplatin-tolerant cells after platinum administration. Here, it is reported that upregulated N 6-methyladenosine (m6A) modification drives the development of resistance in TNBC cells during cisplatin treatment. Mechanistically, histone deacetylase 2 (HDAC2) mediates delactylation of methyltransferase-like 3 (METTL3), facilitating METTL3 interaction with Wilms'-tumor-1-associated protein and subsequently increasing m6A of transcript-associated DNA damage repair. This ultimately promotes cell survival under cisplatin. Furthermore, pharmacological inhibition of HDAC2 using Tucidinostat can enhance the sensitivity of TNBC cells to cisplatin therapy. This study not only elucidates the biological function of lactylated METTL3 in tumor cells but also highlights its negative regulatory effect on cisplatin resistance. Additionally, it underscores the nonclassical functional mechanism of Tucidinostat as a HDAC Inhibitor for improving the efficacy of cisplatin against TNBC.

Keywords

HDAC2; METTL3; TNBC; chemotherapy resistance; lactylation.

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