KDM4 inhibition disrupts the core regulatory transcriptional circuitry in MYCN-driven neuroblastoma [ATAC-seq]

A small set of interconnected lineage-specific transcription factors (TFs) form a core regulatory circuitry (CRC) that establishes and maintains cell identity and grants selective dependencies of distinct cancer types. However, effective therapies to targeting CRC TFs remain lacking. Here, we show that the best-in-class KDM4 inhibitor QC6352 has a potent anticancer activity in MYCN-driven high-risk neuroblastoma and significantly represses the CRC TFs including MYCN, HAND2, ASCL1, PHOX2B by disrupting the super-enhancers that dominate the expression of CRC TFs. Furthermore, we have developed a combination therapy by integrating QC6352 into cytotoxic chemotherapy, which leads to a complete response of MYCN amplified tumors and a better animal survival. This study reveals that targeting histone lysine demethylase 4 family may transform into a therapeutic strategy in clinic for cancers driven by CRC TFs. Overall design: Examination of chromatin accessibility, histone modification post QC6352 treatment in BE2C.

一小簇相互关联的谱系特异性转录因子（lineage-specific transcription factors, TFs）可形成核心调控环路（core regulatory circuitry, CRC），该环路能够建立并维持细胞身份，并赋予不同癌症类型以选择性依赖特性。然而，目前仍缺乏靶向CRC TFs的有效治疗手段。本研究表明，同类最佳的KDM4抑制剂（KDM4 inhibitor）QC6352在MYCN驱动的高危神经母细胞瘤中展现出强效抗癌活性，并通过破坏主导CRC TFs表达的超级增强子（super-enhancers），显著抑制包括MYCN、HAND2、ASCL1、PHOX2B在内的CRC TFs。此外，本研究开发了一种将QC6352与细胞毒性化疗（cytotoxic chemotherapy）联合的治疗方案，该方案可使MYCN扩增型肿瘤实现完全缓解，并改善实验动物的生存期。本研究揭示，靶向组蛋白赖氨酸去甲基化酶4家族（histone lysine demethylase 4 family）或可成为CRC TFs驱动型癌症的临床治疗策略。实验整体设计：检测BE2C细胞经QC6352处理后的染色质可及性（chromatin accessibility）与组蛋白修饰（histone modification）水平。