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

Huang, Gaowei1,2; Liu, Jinwen1; Yu, Anze1; Luo, Chenggong3; Zhu, Jiangquan1; Wang, Yinghan1; Dai, Ziran1; Zhang, Lizhen1; Feng, Zihao1; Lu, Jun1; Dong, Zhong4; Luo, Junhang1; Chen, Wei1; Chen, Zhenhua1

2024-12-01

10.1007/s00018-024-05320-1

CELLULAR AND MOLECULAR LIFE SCIENCES   影响因子和分区

1420-682X

1420-9071

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.

Bladder cancer Cisplatin resistance ISG15 STING pathway

SCI

英语

其他

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:001265511900002

SPRINGER BASEL AG

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Sun Yat Sen Univ, Affiliated Hosp 1, Dept Urol, Guangzhou 510080, Peoples R China
2.Jinan Univ, Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1,Dept Urol,Clin Med Coll 2, Shenzhen 518020, Peoples R China
3.Guizhou Univ, Guizhou Prov Peoples Hosp, Dept Urol, Guiyang 550002, Peoples R China
4.Huizhou Cent Peoples Hosp, Dept Urol, Huizhou 516001, Peoples R China

Huang, Gaowei,Liu, Jinwen,Yu, Anze,et al. Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer[J]. CELLULAR AND MOLECULAR LIFE SCIENCES,2024,81(1).

Huang, Gaowei.,Liu, Jinwen.,Yu, Anze.,Luo, Chenggong.,Zhu, Jiangquan.,...&Chen, Zhenhua.(2024).Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer.CELLULAR AND MOLECULAR LIFE SCIENCES,81(1).

Huang, Gaowei,et al."Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer".CELLULAR AND MOLECULAR LIFE SCIENCES 81.1(2024).