Engineered targeting OIP5 sensitizes bladder cancer to chemotherapy resistance via TRIP12-PPP1CB-YBX1 axis

Wang, Xianteng1,2; Guo, Ting3,4,5; Niu, Liman1; Zheng, Binbin1; Huang, Wei6; Xu, Haibo1; Huang, Weiren1,3,4

2024-08-01

10.1038/s41388-024-03136-8

ONCOGENE   影响因子和分区

0950-9232

1476-5594

Chemoresistance is an important cause of treatment failure in bladder cancer, and identifying genes that confer drug resistance is an important step toward developing new therapeutic strategies to improve treatment outcomes. In the present study, we show that gemcitabine plus cisplatin (GEM/DDP) therapy induces NF-kappa B signaling, which promotes p65-mediated transcriptional activation of OIP5. OIP5 recruits the E3 ubiquitin ligase TRIP12 to bind to and degrade the phosphatase PPP1CB, thereby enhancing the transcription factor activity of YBX1. This in turn upregulates drug-resistance-related genes under the transcriptional control of YBX1, leading to chemoresistance. Moreover, PPP1CB degradation can enhance the phosphorylation activity of IKK beta, triggering the NF-kappa B signaling cascade, which further stimulates OIP5 gene expression, thus forming a negative feedback regulatory loop. Consistently, elevated OIP5 expression was associated with chemoresistance and poor prognosis in patients with bladder cancer. Furthermore, we used a CRISPR/Cas9-based engineered gene circuit, which can monitor the progression of chemoresistance in real-time, to induce OIP5 knockout upon detection of increased NF-kappa B signaling. The gene circuit significantly inhibited tumor cell growth in vivo, underscoring the potential for synergy between gene therapy and chemotherapy in the treatment of cancer.

SCI

英语

其他

National Key RD Program of China (2019YFA0906000) Guangdong Special Support Program (2021JC06Y578) Shenzhen Portion of Shenzhen-Hong Kong Science and Technology Innovation Cooperation Zone (HTHZQSWS- KCCYB-2023060) Sanming Project of the Shenzhen Health a[2019YFA0906000] ; National Key R&D Program of China[HTHZQSWS- KCCYB-2023060] ; Shenzhen-Hong Kong Science and Technology Innovation Cooperation Zone[82203459] ; National Natural Science Foundation of China[2021JC06Y578] ; Fundamental Research Funds for the Central Universities[59000-31610020] ; Sun Yat-sen University[CJGJZD20200617102403009] ; Shenzhen Municipal Government of China[SZSM202011017] ; Shenzhen High-Level Hospital Construction Fund[ZTXM20214005] ; Shenzhen Institute of Synthetic Biology Scientific Research Program[SZXK020] ; Shenzhen Key Medical Discipline Construction Fund[2023T160436]

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

WOS:001292776800002

SPRINGERNATURE

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Int Canc Ctr,Dept Urol,Shenzhen Inst Translat Med,, Shenzhen, Peoples R China
2.Sun Yat Sen Univ, Mol Canc Res Ctr, Sch Med, Shenzhen Campus, Shenzhen, Peoples R China
3.Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen Inst Synthet Biol, Shenzhen, Peoples R China
4.Shenzhen Univ, Shenzhen Peoples Hosp 2, Affiliated Hosp 1, Guangdong Key Lab Syst Biol & Synthet Biol Urogeni, Shenzhen, Peoples R China
5.Guangxi Univ Chinese Med, Grad Sch, Nanning, Peoples R China
6.Southern Univ Sci & Technol, Dept Biol, Shenzhen, Guangdong, Peoples R China

Wang, Xianteng,Guo, Ting,Niu, Liman,et al. Engineered targeting OIP5 sensitizes bladder cancer to chemotherapy resistance via TRIP12-PPP1CB-YBX1 axis[J]. ONCOGENE,2024.

Wang, Xianteng.,Guo, Ting.,Niu, Liman.,Zheng, Binbin.,Huang, Wei.,...&Huang, Weiren.(2024).Engineered targeting OIP5 sensitizes bladder cancer to chemotherapy resistance via TRIP12-PPP1CB-YBX1 axis.ONCOGENE.

Wang, Xianteng,et al."Engineered targeting OIP5 sensitizes bladder cancer to chemotherapy resistance via TRIP12-PPP1CB-YBX1 axis".ONCOGENE (2024).