2. Academic Validation
  3. Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer

Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer

  • Cell Mol Life Sci. 2024 Jul 8;81(1):292. doi: 10.1007/s00018-024-05320-1.
Gaowei Huang # 1 2,  Jinwen Liu # 1,  Anze Yu # 1,  Chenggong Luo # 3,  Jiangquan Zhu 1,  Yinghan Wang 1,  Ziran Dai 1,  Lizhen Zhang 1,  Zihao Feng 1,  Jun Lu 1,  Zhong Dong 4,  Junhang Luo 5,  Wei Chen 6,  Zhenhua Chen 7
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 2 Department of Urology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China.
  • 3 Department of Urology, Guizhou Provincial People's Hospital, Guizhou University, Guiyang, 550002, China.
  • 4 Department of Urology, Huizhou Central People's Hospital, Huizhou, 516001, China. hzdongzhong@126.com.
  • 5 Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. luojunh@mail.sysu.edu.cn.
  • 6 Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. chenw3@mail.sysu.edu.cn.
  • 7 Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. chenzhh75@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 38976080 DOI: 10.1007/s00018-024-05320-1
Abstract

Cisplatin resistance is a major challenge for systemic therapy against advanced bladder Cancer (BC). Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a serine/threonine protein Phosphatase 2 A regulatory subunit), in BC promoted cell proliferation and migration. What's more, low PPP2R2B expression was correlated with cisplatin resistance. In vitro and in vivo experiments verified that PPP2R2B could promote BC sensitivity to cisplatin. In terms of mechanism, we identified a novel function of PPP2R2B as a nucleocytoplasmic transport molecule. PPP2R2B promoted ISG15 entry into the nucleus by mediating binding of IPO5 with ISG15. Nuclear translocation of ISG15 inhibited DNA repair, further increasing ISG15 expression through activation of the STING pathway. Besides, PPP2R2B was down-regulated by SUV39H1-mediated histone 3 lysine 9 trimethylation, which could be restored by the SUV39H1-specific inhibitor, chaetocin. Our data suggest that PPP2R2B expression level is a potential biomarker for chemotherapy response and that chemotherapy in combination with chaetocin may be a feasible treatment strategy for patients with BC.

Keywords

Bladder cancer; Cisplatin resistance; ISG15; PPP2R2B; STING pathway.

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