Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression.
Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression.
复制标题
组蛋白去甲基化酶JMJD2D通过增强EpCAM和Sox9表达促进肝癌干细胞样细胞的自我更新
DOI：
10.1074/jbc.ra120.015335
复制
发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Yu C
中科院分区：
文献类型：
--
作者：
Deng Y;Li M;Zhuo M;Guo P;Chen Q;Mo P;Li W;Yu C
癌症干细胞样细胞（CSC）有助于肿瘤异质性、转移、治疗抗性和复发的高发生率。组蛋白赖氨酸脱甲基酶4D（KDM 4D或JMJD 2D）在结肠和肝脏肿瘤中高度表达，促进癌症进展;然而，JMJD 2D在CSC中的作用仍不清楚。在这里，我们发现，JMJD 2D表达增加，在肝癌干细胞样细胞（LCSCs）;下调JMJD 2D抑制LCSCs在体外和体内的自我更新，并通过减少循环LCSCs的存活和早期肺种植来抑制LCSCs的肺转移。JMJD 2D通过增强CSC标志物EpCAM和Sox 9的表达促进LCSC自我更新; JMJD 2D通过分别与β-catenin/TCF 4和Notch 1胞内结构域相互作用降低EpCAM和Sox 9启动子上的H3 K9 me 3水平以增强其转录。在JMJD 2D敲低的肝癌细胞中EpCAM和Sox 9表达的恢复拯救了LCSC的自我更新。使用5-c-8HQ的JMJD 2D的药理学抑制减少了LCSC的自我更新和肝癌进展。总的来说，我们的研究结果表明，JMJD 2D通过Wnt/β-catenin和Notch信号通路增强EpCAM和Sox 9表达来促进LCSC自我更新，并且是肝癌的潜在治疗靶点。
Cancer stem-like cells (CSCs) contribute to the high rate of tumor heterogeneity, metastasis, therapeutic resistance, and recurrence. Histone lysine demethylase 4D (KDM4D or JMJD2D) is highly expressed in colon and liver tumors, where it promotes cancer progression; however, the role of JMJD2D in CSCs remains unclear. Here, we show that JMJD2D expression was increased in liver cancer stem-like cells (LCSCs); downregulation of JMJD2D inhibited the self-renewal of LCSCs in vitro and in vivo and inhibited the lung metastasis of LCSCs by reducing the survival and the early lung seeding of circulating LCSCs. Mechanistically, JMJD2D promoted LCSC self-renewal by enhancing the expression of CSC markers EpCAM and Sox9; JMJD2D reduced H3K9me3 levels on the promoters of EpCAM and Sox9 to enhance their transcription via interaction with β-catenin/TCF4 and Notch1 intracellular domain, respectively. Restoration of EpCAM and Sox9 expression in JMJD2D-knockdown liver cancer cells rescued the self-renewal of LCSCs. Pharmacological inhibition of JMJD2D using 5-c-8HQ reduced the self-renewal of LCSCs and liver cancer progression. Collectively, our findings suggest that JMJD2D promotes LCSC self-renewal by enhancing EpCAM and Sox9 expression via Wnt/β-catenin and Notch signaling pathways and is a potential therapeutic target for liver cancer.