Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities [RNA-Seq]

Transcriptional coregulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies. Overall design: Comparative gene expression profiling analysis of SLAM-seq and 3' end mRNA-seq data for BE2C cells with HDAC1/2 inhibition and HDAC2 degradation.

转录共调节因子（transcriptional coregulators）作为靶向干预致癌基因调控程序的靶点已被广泛研究。然而，该靶点类别中的诸多蛋白质普遍为细胞存活所必需，这可能限制候选药物可实现的治疗窗口。通过分析大规模基于CRISPR/Cas9的必需性筛选数据集，我们发现组蛋白去乙酰化酶1（HDAC1）与HDAC2之间存在遗传相互作用：二者的旁系同源基因彼此发生半合子缺失时会产生合成致死效应。这种附带合成致死现象由发生于多种实体瘤和血液系统恶性肿瘤（包括神经母细胞瘤与多发性骨髓瘤）中的复发性染色体易位所介导。我们借助基因敲除或dTAG介导的降解实验证实，HDAC2功能缺失可在体内外抑制HDAC1缺陷型神经母细胞瘤的生长。从机制层面来看，我们发现于此类细胞中靶向降解HDAC2会促使核小体重塑与去乙酰化酶（NuRD）复合物的多个亚基发生降解，进而降低基因组中HDAC2/NuRD结合位点的染色质开放性，并削弱对增强子相关转录的调控。此外，我们揭示多个被降解的NuRD复合物亚基正是神经母细胞瘤与多发性骨髓瘤的细胞存活依赖基因，这为开发旁系同源选择性HDAC1或HDAC2降解剂提供了研究动机。综上，我们将HDAC1/2附带合成致死效应鉴定为全新的治疗靶点，并揭示了一种利用NuRD相关癌症基因依赖的新型机制。整体实验设计：对经HDAC1/2抑制与HDAC2降解处理的BE2C细胞，开展SLAM-seq与3'端mRNA测序数据的比较基因表达谱分析。