Histone demethylase KDM3A is required for enhancer activation of hippo target genes in colorectal cancer
Histone demethylase KDM3A is required for enhancer activation of hippo target genes in colorectal cancer
复制标题
结直肠癌中 hippo 靶基因的增强子激活需要组蛋白去甲基化酶 KDM3A
DOI：
10.1093/nar/gky1317
复制
发表时间：
2019-03-18
影响因子：
14.9
通讯作者：
Wu, Min
中科院分区：
文献类型：
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作者：
Wang, Hui-Yi;Long, Qiao-Yun;Wu, Min
摘要Hippo通路参与肿瘤的发生，其在胞浆中的调控已被广泛研究，但其在核中的调控机制尚不清楚。在目前的研究中，使用血清饥饿后的FBS诱导模型，我们确定了KDM 3A，组蛋白H3 K9 me 1/2的脱甲基酶，作为河马靶基因的正调节因子。KDM 3A通过两种机制促进基因表达，一种是上调YAP 1的表达，另一种是促进H3 K27 ac对hippo靶基因的增强子。H3 K27 ac上调与基因激活更相关，但与H3 K4 me 3无关; KDM 3A缺失导致H3 K9 me 2上调主要在TEAD 1结合增强子而不是基因体上，进一步导致H3 K27 ac减少，TEAD 1结合增强子和转录受损。此外，KDM 3A与p300相关，并且是p300募集到增强子所必需的。KDM 3A缺陷延迟癌细胞生长和迁移，这被YAP 1表达所拯救。结直肠癌组织中KDM 3A的表达与YAP 1和hippo靶基因相关，可作为结直肠癌患者预后的潜在指标。总之，我们的研究揭示了河马信号和增强子激活的新机制，这对结直肠癌的肿瘤发生至关重要。
Abstract Hippo pathway is involved in tumorigenesis, and its regulation in cytosol has been extensively studied, but its regulatory mechanisms in the nuclear are not clear. In the current study, using a FBS-inducing model following serum starvation, we identified KDM3A, a demethylase of histone H3K9me1/2, as a positive regulator for hippo target genes. KDM3A promotes gene expression through two mechanisms, one is to upregulate YAP1 expression, and the other is to facilitate H3K27ac on the enhancers of hippo target genes. H3K27ac upregulation is more relevant with gene activation, but not H3K4me3; and KDM3A depletion caused H3K9me2 upregulation mainly on TEAD1-binding enhancers rather than gene bodies, further resulting in H3K27ac decrease, less TEAD1 binding on enhancers and impaired transcription. Moreover, KDM3A is associated with p300 and required for p300 recruitment to enhancers. KDM3A deficiency delayed cancer cell growth and migration, which was rescued by YAP1 expression. KDM3A expression is correlated with YAP1 and hippo target genes in colorectal cancer patient tissues, and may serve as a potential prognosis mark. Taken together, our study reveals novel mechanisms for hippo signaling and enhancer activation, which is critical for tumorigenesis of colorectal cancer.