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BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair

Oncogene volume 40, pages 2711–2724 (2021)Cite this article

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Abstract

Cisplatin-based chemoradiotherapy is the recommended treatment for local advanced cervical cancer, but radioresistance remains one of the most important and unresolved clinical problems. Investigations have revealed aberrant epigenetic modifications as one of the chief culprits for the development of radioresistance. Here, we attempt to identify a radiosensitizer from an epigenetic drug synergy screen and explore the underlying mechanism. We integrated epigenetic inhibitors and radiotherapy in cervical cancer cell lines to identify potential radiosensitizers. We further verified the sensitization effect of the drug and the function of its target gene both in vitro and in vivo. Finally, we validated the clinical significance of its target gene in clinical cervical cancer specimens. We identified JQ1, a BRD4 inhibitor, as a potent radiosensitizer. Functional assays demonstrated that repressing BRD4 activity led to significant radiosensitization and potentiation of DNA damage in cervical cancer cell lines. By using RNA-seq to determine JQ1-mediated changes in transcription, we identified RAD51AP1 as a major BRD4 target gene involved in radiosensitivity. A dual-luciferase reporter assay and ChIP-qPCR showed that BRD4 binds to the promoter region of RAD51AP1 and promotes its transcription, whereas this activity was attenuated by BRD4 inhibition. The in vivo experiments also suggested a synergy between BRD4 inhibition and radiotherapy. High BRD4 expression was found to be related to a worse prognosis and radiation resistance. BRD4 inhibition sensitizes cervical cancer to radiotherapy by inhibiting RAD51AP1 transcription. The combination of JQ1 with radiotherapy merits further evaluation as a therapeutic strategy for improving local control in cervical cancer.

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Fig. 1: Epigenetic inhibitors screening identifies JQ1 as a potent radiosensitizer.
Fig. 2: JQ1 enhances IR-induced apoptosis and DNA damage.
Fig. 3: Knockdown of BRD4 sensitizes cervical cancer to radiotherapy.
Fig. 4: JQ1 represses transcription of RAD51AP1 via BRD4 inhibition.
Fig. 5: RAD51AP1 downregulation sensitizes cervical cancer to radiotherapy, while RAD51AP1 overexpression rescues BRD4 inhibition-induced phenotype.
Fig. 6: BRD4 expression predicts prognosis of uterine cervical cancer.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China to XW (No. 81672569), the Natural Science Foundation of Shanghai to GK (No. 19ZR1410700), and the National Natural Science Foundation of China to JL (No. 81902660).

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  1. These authors contributed equally: Mengdong Ni, Jiajia Li, Haiyun Zhao

Authors and Affiliations

  1. Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

    Mengdong Ni, Jiajia Li, Haiyun Zhao, Fei Xu, Jingyi Cheng, Min Yu, Guihao Ke & Xiaohua Wu

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Mengdong Ni, Jiajia Li, Haiyun Zhao, Fei Xu, Jingyi Cheng, Min Yu, Guihao Ke & Xiaohua Wu

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Ni, M., Li, J., Zhao, H. et al. BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair. Oncogene 40, 2711–2724 (2021). https://doi.org/10.1038/s41388-021-01735-3

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