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ARID1A Inactivation Increases Expression of circ0008399 and Promotes Cisplatin Resistance in Bladder Cancer

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An Erratum to this article was published on 04 December 2023

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Abstract

Objective

Cisplatin (CDDP)-based chemotherapy is a first-line, drug regimen for muscle-invasive bladder cancer (BC) and metastatic bladder cancer. Clinically, resistance to CDDP restricts the clinical benefit of some bladder cancer patients. AT-rich interaction domain 1A (ARID1A) gene mutation occurs frequently in bladder cancer; however, the role of CDDP sensitivity in BC has not been studied.

Methods

We established ARID1A knockout BC cell lines using CRISPR/Cas9 technology. IC50 determination, flow cytometry analysis of apoptosis, and tumor xenograft assays were performed to verify changes in the CDDP sensitivity of BC cells losing ARID1A. qRT-PCR, Western blotting, RNA interference, bioinformatic analysis, and ChIP-qPCR analysis were performed to further explore the potential mechanism of ARID1A inactivation in CDDP sensitivity in BC.

Results

It was found that ARID1A inactivation was associated with CDDP resistance in BC cells. Mechanically, loss of ARID1A promoted the expression of eukaryotic translation initiation factor 4A3 (EIF4A3) through epigenetic regulation. Increased expression of EIF4A3 promoted the expression of hsa_circ_0008399 (circ0008399), a novel circular RNA (circRNA) identified in our previous study, which, to some extent, showed that ARID1A deletion caused CDDP resistance through the inhibitory effect of circ0008399 on the apoptosis of BC cells. Importantly, EIF4A3-IN-2 specifically inhibited the activity of EIF4A3 to reduce circ0008399 production and restored the sensitivity of ARID1A inactivated BC cells to CDDP.

Conclusion

Our research deepens the understanding of the mechanisms of CDDP resistance in BC and elucidates a potential strategy to improve the efficacy of CDDP in BC patients with ARID1A deletion through combination therapy targeting EIF4A3.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yang-kai Jiang, Yu-jun Shuai, Hui Zhang, Chao Huang, Liang Wang, Jia-yin Sun, Wen-jie Wei, Xing-yuan Xiao & Guo-song Jiang

  2. Department of Urology, Jingshan Union Hospital of Huazhong University of Science and Technology (People’s Hospital of Jingshan), Jingshan, 431899, China

    Hua-min Ding

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  1. Yang-kai Jiang
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Correspondence to Xing-yuan Xiao or Guo-song Jiang.

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Conflict of Interest Statement

The authors declare that they have no conflicts of interest.

This work was supported by grants from the National Natural Science Foundation of China (No. 81974396, No. 81874091, No. 82072840, and No. 82102734), the Natural Science Foundation of Hubei Province (No. 2020CFB829), and the Health Commission of Hubei Province Scientific Research Project (No. WJ2021F081).

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Jiang, Yk., Shuai, Yj., Ding, Hm. et al. ARID1A Inactivation Increases Expression of circ0008399 and Promotes Cisplatin Resistance in Bladder Cancer. CURR MED SCI 43, 560–571 (2023). https://doi.org/10.1007/s11596-023-2731-8

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