PAX9 Determines Epigenetic State Transition and Cell Fate in Cancer.
PAX9 Determines Epigenetic State Transition and Cell Fate in Cancer.
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DOI：
10.1158/0008-5472.can-21-1114
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发表时间：
2021-09-15
期刊：
影响因子：
11.2
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Zhao Z;Szczepanski AP;Tsuboyama N;Abdala-Valencia H;Goo YA;Singer BD;Bartom ET;Yue F;Wang L
小细胞肺癌的全基因组筛查揭示了PAX9/NuRD介导的表观遗传增强子沉默和肿瘤进展，支持针对PAX9调节的网络的新型个性化治疗方法的开发。基因和表观遗传修饰的异常可能导致与各种癌症类型相关的基因表达谱的急剧变化。小细胞肺癌(SCLC)是一种侵袭性和致命性的肺癌，目前有效的治疗方法有限。通过在SCLC细胞中进行全基因组CRISPR-Cas9缺失筛查，我们发现配对盒蛋白9(PAX9)是一种在人类恶性SCLC肿瘤样本中过表达的基本因子，由BAP1/ASXL3/BRD4表观遗传轴转录驱动。全基因组研究表明，PAX9占据了远端的增强子元件，并通过限制增强子的活性来抑制基因的表达。在多个小细胞肺癌细胞系中，PAX9的基因缺失导致显著诱导启动-活性增强子转变，导致大量神经分化和肿瘤抑制基因的表达增加。在机制上，PAX9与核小体重塑和脱乙酰酶(NuRD)复合体在增强子上相互作用和协同作用，以抑制邻近基因的表达，这一作用可被药物的HDAC抑制逆转。总之，这项研究从机制上深入了解了人小细胞肺癌中PAX9/NuRD复合体表观遗传轴的致癌功能，并提示启动增强子的重新激活可能在治疗高表达PAX9的小细胞肺癌方面具有潜在的治疗效果。小细胞肺癌的全基因组筛查揭示了PAX9/NuRD介导的表观遗传增强子沉默和肿瘤进展，支持针对PAX9调节的网络的新型个性化治疗方法的开发。
A genome-wide screen in small cell lung cancer reveals PAX9/NuRD-mediated epigenetic enhancer silencing and tumor progression, supporting the development of novel personalized therapeutic approaches targeting the PAX9-regulated network. Abnormalities in genetic and epigenetic modifications can lead to drastic changes in gene expression profiles that are associated with various cancer types. Small cell lung cancer (SCLC) is an aggressive and deadly form of lung cancer with limited effective therapies currently available. By utilizing a genome-wide CRISPR-Cas9 dropout screen in SCLC cells, we identified paired box protein 9 (PAX9) as an essential factor that is overexpressed in human malignant SCLC tumor samples and is transcriptionally driven by the BAP1/ASXL3/BRD4 epigenetic axis. Genome-wide studies revealed that PAX9 occupies distal enhancer elements and represses gene expression by restricting enhancer activity. In multiple SCLC cell lines, genetic depletion of PAX9 led to significant induction of a primed-active enhancer transition, resulting in increased expression of a large number of neural differentiation and tumor-suppressive genes. Mechanistically, PAX9 interacted and cofunctioned with the nucleosome remodeling and deacetylase (NuRD) complex at enhancers to repress nearby gene expression, which was reversed by pharmacologic HDAC inhibition. Overall, this study provides mechanistic insight into the oncogenic function of the PAX9/NuRD complex epigenetic axis in human SCLC and suggests that reactivation of primed enhancers may have potential therapeutic efficacy in treating SCLC expressing high levels of PAX9. A genome-wide screen in small cell lung cancer reveals PAX9/NuRD-mediated epigenetic enhancer silencing and tumor progression, supporting the development of novel personalized therapeutic approaches targeting the PAX9-regulated network.