Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
Hangzhou Innovation Institute for Systems Oncology (HIISCO), 3F Building 1, 2636 Yuhangtang Rd, Yuhang District, Hangzhou, 311121, Zhejiang Province, China.
Oncogene. 2022 Mar;41(10):1397-1409. doi: 10.1038/s41388-022-02176-2. Epub 2022 Jan 11.
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.
肝细胞癌（HCC）由于缺乏有效的全身治疗方法，已成为癌症相关死亡的第三大原因。基因组 DNA 测序显示 ARID2 基因（编码 SWI/SNF 染色质重塑复合物亚基的基因）失活突变频率很高，然而，ARID2 突变的 HCC 患者的治疗策略仍完全不清楚。在这项研究中，我们首先使用由 2180 种 FDA 批准的药物和其他化合物组成的化合物文库进行高通量筛选，以引出针对 ARID2 缺陷 HCC 细胞的合成致死潜在药物。有趣的是，BRD4 蛋白的选择性抑制剂 JQ1 独特地抑制了 ARID2 缺陷 HCC 细胞的生长。接下来，通过加剧 DNA 损伤，尤其是双链断裂（DSB），进一步证实 JQ1 主要通过 ARID2 耗竭诱导细胞致死。功能测定表明，BRD4 抑制和 ARID2 缺失协同抑制两种主要的 DNA 损伤修复途径，同源重组（HR）和非同源末端连接（NHEJ），通过削弱 BRCA1、RAD51 和 53BP1 的转录，这些基因编码负责 DSB 修复的核心分子。从机制上讲，ARID2 和 BRD4 协同作用以维持这些基因在染色质构象中的转录增强子-启动子环。然而，由于 ARID2 和 BRD4 均被破坏，这些 DNA 修复相关基因在应对 DNA 损伤时的表达受到阻碍，导致 DSB 积累和细胞凋亡。总之，这项研究揭示了 BRD4 抑制可能在 ARID2 缺陷 HCC 细胞中诱导合成致死，这可能为 ARID2 突变的 HCC 患者提供一种潜在的治疗策略。
