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BRD4 inhibition induces synthetic lethality in ARID2-deficient hepatocellular carcinoma by increasing DNA damage

Oncogene volume 41, pages 1397–1409 (2022)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) has emerged as the third cause of cancer-related death owing to lacking effective systemic therapies. Genomic DNA sequencing revealed the high frequency of loss-of-function mutations in ARID2, which encodes a subunit of SWI/SNF chromatin remodeling complex, however, the therapeutic strategy for the HCC patients with ARID2 mutations is still completely unclear. In this study, we first performed a high-throughput screening approach using a compound library consisting of 2 180 FDA-approved drugs and other compounds, to elicit the potential drugs for synthetic lethality to target ARID2-deficient HCC cells. Interestingly, JQ1, a selective inhibitor of bromodomain protein BRD4, uniquely suppressed the growth of ARID2- deficient HCC cells. Next JQ1 is further confirmed to predominantly induce cell lethality upon ARID2 depletion through exacerbating DNA damage, especially double strand breaks (DSBs). Functional assays demonstrated that both BRD4 inhibition and ARID2 deficiency synergistically impede two main DNA damage repair pathways, homologous recombination (HR) and non-homologous end-joining (NHEJ), through attenuating the transcription of BRCA1, RAD51, and 53BP1, which encode the core molecules responsible for DSB repair. Mechanistically, both ARID2 and BRD4 exert a synergistic effect for maintaining transcriptional enhancer-promoter loops of these genes within chromatin conformation. However, as both ARID2 and BRD4 are disrupted, the expression of these DNA repair-related genes in response to DNA damage are hindered, resulting in DSB accumulation and cell apoptosis. Taken together, this study discloses that BRD4 inhibition may induce synthetic lethality in ARID2-deficient HCC cells, which might provide a potential therapeutic strategy for HCC patients with ARID2 mutations.

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Fig. 1: ARID2-deficient cells are hypersensitive to BET inhibitor JQ1.
Fig. 2: BRD4 inhibition confers the synthetic lethality to ARID2 deficiency in HCC cells.
Fig. 3: BRD4 inhibitor JQ1 induces the accumulation of DNA damage and cell apoptosis in ARID2-deficient HCC cells.
Fig. 4: BRD4 inhibitor JQ1 decreases HR and NHEJ activities in ARID2-deficient cells.
Fig. 5: JQ1 represses the enhancer and promoter activities of BRCA1, RAD51, and 53BP1.
Fig. 6: Both ARID2 deficiency and BRD4 inhibition synergistically impair the enhancer-promoter interactions of BRCA1, RAD51, and 53BP1.
Fig. 7: JQ1 efficiently suppresses ARID2-deficient HCC tumors in vivo.

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Acknowledgements

We thank all members of Han Lab for helpful discussions on the project. This work was supported by Grants from the National Natural Science Foundation of China (82073116 and 81672772 to ZH), National Key Research and Development Program of China (2020YFC2002705 to ZH), Natural Science Foundation of Shanghai (19140902500 to ZH), National Science and Technology Major Project (2017ZX10203207 to ZH) and Shanghai Jiao Tong University Scientific and Technological Innovation Funds (2019TPA09 and ZH2018ZDA33 to ZH).

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  1. These authors contributed equally: Dan-Dan He, Xue-Ying Shang, Na Wang.

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  1. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China

    Dan-Dan He, Xue-Ying Shang, Na Wang, Guang-Xing Wang, Kun-Yan He, Lan Wang & Ze-Guang Han

  2. Hangzhou Innovation Institute for Systems Oncology (HIISCO), 3F Building 1, 2636 Yuhangtang Rd, Yuhang District, Hangzhou, 311121, Zhejiang Province, China

    Ze-Guang Han

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ZGH, DDH, and XYS conceived and designed this study; DDH, XYS, NW, GXW, KYH, and LW performed experiments and acquired data; DDH, XYS analyzed data and wrote manuscript; ZGH substantively revised the manuscript; ZGH supervised the project. All authors read and approved the final manuscript.

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Correspondence to Ze-Guang Han.

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He, DD., Shang, XY., Wang, N. et al. BRD4 inhibition induces synthetic lethality in ARID2-deficient hepatocellular carcinoma by increasing DNA damage. Oncogene 41, 1397–1409 (2022). https://doi.org/10.1038/s41388-022-02176-2

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