2. Academic Validation
  3. The RNA-stability-independent role of the RNA m6A reader YTHDF2 in promoting protein translation to confer tumor chemotherapy resistance

The RNA-stability-independent role of the RNA m6A reader YTHDF2 in promoting protein translation to confer tumor chemotherapy resistance

  • Mol Cell. 2025 Jun 19;85(12):2320-2336.e9. doi: 10.1016/j.molcel.2025.05.015.
Tao Liu 1,  Dan Yang 2,  Qinglv Wei 2,  Yuan Wang 2,  Lei Tian 3,  Xiaoyi Liu 2,  Yu Yang 2,  Qingya Luo 4,  Jie Xu 1,  Yujiao Liu 2,  Chenyue Yang 2,  Xinzhao Zuo 2,  Fatao Luo 1,  Xin Luo 1,  Hongyan Zhao 2,  Li Li 5,  Jing Xu 2,  Jia Yu 6,  Shoubao Ma 7,  Jianhua Yu 8,  Ping Yi 9
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China; Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China.
  • 2 Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China.
  • 3 Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA.
  • 4 Department of Pathology, Southwest Hospital, Army Medical University, Chongqing 401120, China.
  • 5 Department of Obstetrics and Gynecology, Daping Hospital, Army Medical University, Chongqing 400042, China.
  • 6 Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing 100021, China.
  • 7 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91008, USA. Electronic address: shma@coh.org.
  • 8 Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: jianhuay@uci.edu.
  • 9 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China; Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China. Electronic address: yiping@cqmu.edu.cn.
PMID: 40480228 DOI: 10.1016/j.molcel.2025.05.015
Abstract

N6-methyladenosine (m6A) modification plays pivotal roles in myriad biological processes. The YTH domain family protein YTHDF2, recognized as an m6A "reader" protein, is primarily associated with the canonical function of facilitating RNA degradation. Nevertheless, the intricate non-decay regulatory mechanism exerted by YTHDF2 remains enigmatic. Here, using ovarian Cancer as a model, we demonstrate that YTHDF2 forms a tangible interaction with the eukaryotic translation initiation factor eIF3F and the RNA helicase DDX1, thereby enhancing protein synthesis in tumor cells. Instead of promoting RNA degradation, YTHDF2 facilitates the translation of m6A-modified mRNAs encoding microtubule-associated proteins, which drives Cancer progression and reduces the chemosensitivity of Cancer cells to paclitaxel, a commonly used chemotherapy drug. Notably, through virtual screening, we identified a YTHDF2-specific small-molecule inhibitor. Therapeutic targeting of YTHDF2 with this inhibitor effectively suppresses protein translation in tumor cells and reverses paclitaxel resistance.

Keywords

YTHDF2; m(6)A; translational regulation; tumor resistance.

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