Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene, which is frequently mutated in breast and ovarian cancers. BRCA1 plays a key role in the homologous recombination directed DNA repair, allowing its deficiency to act as a therapeutic target of DNA damaging agents. In this study, we found that inhibition of the class I histone deacetylases (HDAC) exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells. Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein (TXNIP), causing reactive oxygen species (ROS)-mediated DNA damage. This effect induced preferential apoptosis in BRCA1 -/- breast cancer cells where DNA repair system is compromised. Two animal experiments and gene expression-associated patients' survival analysis further confirmed in vivo synthetic lethality between BRCA1 and HDAC. Finally, the combination of inhibitors of HDAC and bromodomain and extra-terminal motif (BET), another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage, showed a strong anticancer effect in BRCA1 -/- breast cancer cells. Together, this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries, HDAC and BET.

中文翻译：

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I类组蛋白脱乙酰基酶抑制作用是合成致死性乳腺癌细胞中BRCA1缺乏症。

乳腺癌易感基因1（BRCA1）是抑癌基因，在乳腺癌和卵巢癌中经常发生突变。BRCA1在同源重组指导的DNA修复中起着关键作用，使其缺乏可作为DNA损伤剂的治疗靶标。在这项研究中，我们发现抑制I类组蛋白脱乙酰基酶（HDAC）在乳腺癌细胞中具有BRCA1缺乏的合成致死性。转录组分析和验证研究表明，HDAC抑制增强了硫氧还蛋白相互作用蛋白（TXNIP）的表达，从而导致了活性氧（ROS）介导的DNA损伤。这种作用在DNA修复系统受损的BRCA1-/-乳腺癌细胞中诱导了优先凋亡。两项动物实验和与基因表达相关的患者 生存分析进一步证实了BRCA1和HDAC之间的体内合成杀伤力。最后，HDAC和溴结构域抑制剂以及末端外基序（BET）的抑制剂（另一种也通过氧化应激介导的DNA损伤起作用的BRCA1合成致死靶标）的组合在BRCA1-/-乳腺癌细胞中显示出强大的抗癌作用。总之，这项研究通过针对两种表观遗传机制，即HDAC和BET，为BRCA1缺陷型乳腺癌提供了一种新的治疗策略。