2. Academic Validation
  3. The deubiquitinase USP9X and E3 ligase WWP1 orchestrate IGF2BP2 ubiquitination homeostasis to drive TNBC progression and cisplatin sensitivity

The deubiquitinase USP9X and E3 ligase WWP1 orchestrate IGF2BP2 ubiquitination homeostasis to drive TNBC progression and cisplatin sensitivity

  • Cell Death Dis. 2025 Oct 6;16(1):703. doi: 10.1038/s41419-025-08038-5.
Tian Xia # 1,  Jianyi Zhao # 1,  Zhengyu Zhang # 1,  Weilin Lu 1,  Yuxin Wang 1,  Xinrui Dong 1,  Mingyi Sang 1,  Linjie Ju 2,  Xu Zhang 3,  Jifu Wei 4,  Qiang Ding 5
Affiliations

Affiliations

  • 1 Jiangsu Breast Disease Center & Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
  • 2 Department of Pharmacy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
  • 3 Jiangsu Breast Disease Center & Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. zhangxu2017@njmu.edu.cn.
  • 4 Department of Pharmacy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. weijifu@njmu.edu.cn.
  • 5 Jiangsu Breast Disease Center & Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. dingqiang@njmu.edu.cn.
  • # Contributed equally.
PMID: 41053085 DOI: 10.1038/s41419-025-08038-5
Abstract

The functional impact of post-translational modifications (PTMs) on many N6-methyladenosine (m6A) regulatory proteins remains unclear. Our previous study demonstrated that the m6A reader IGF2BP2 drives triple-negative breast Cancer (TNBC) progression through epigenetic regulation. Here, we found that IGF2BP2 ubiquitination homeostasis was dynamically regulated by the opposing actions of USP9X (Deubiquitinase) and WWP1 (E3 Ligase). We further identified USP9X as a cisplatin-binding protein, whose inactivation upon cisplatin treatment shifts this balance toward WWP1-mediated IGF2BP2 degradation in TNBC. This suppressed IGF2BP2-mediated stabilization and translation of m6A-modified MYC/CDK6 mRNAs, thereby inhibiting TNBC progression. Notably, combined USP9X inhibitor WP1130 and low-dose cisplatin showed synergistic therapeutic efficacy against TNBC in both in vivo and in vitro models. Overall, our findings established that the USP9X/WWP1 axis maintained IGF2BP2 ubiquitination homeostasis to regulate m6A-dependent oncogenic functions in TNBC. Crucially, cisplatin uniquely disrupts this balance through USP9X binding, impairing IGF2BP2's m6A recognition capacity and revealing a novel UPS-mediated drug response mechanism specific to TNBC treatment.

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