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.

中文翻译：

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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


癌症干细胞样细胞（CSC）导致肿瘤异质性、转移、治疗耐药和复发率较高。组蛋白赖氨酸脱甲基酶 4D（KDM4D 或 JMJD2D）在结肠癌和肝脏肿瘤中高表达，可促进癌症进展；然而，JMJD2D 在 CSC 中的作用仍不清楚。在这里，我们发现肝癌干样细胞（LCSC）中 JMJD2D 表达增加； JMJD2D 的下调在体外和体内抑制 LCSC 的自我更新，并通过降低循环 LCSC 的存活率和早期肺播种来抑制 LCSC 的肺转移。从机制上讲，JMJD2D通过增强CSC标志物EpCAM和Sox9的表达来促进LCSC自我更新； JMJD2D 降低 EpCAM 和 Sox9 启动子上的 H3K9me3 水平，从而通过分别与 β-catenin/TCF4 和 Notch1 胞内结构域相互作用来增强其转录。 JMJD2D 敲低肝癌细胞中 EpCAM 和 Sox9 表达的恢复挽救了 LCSC 的自我更新。使用 5-c-8HQ 对 JMJD2D 进行药理学抑制可减少 LCSC 的自我更新和肝癌进展。总的来说，我们的研究结果表明，JMJD2D 通过 Wnt/β-catenin 和 Notch 信号通路增强 EpCAM 和 Sox9 的表达来促进 LCSC 自我更新，是肝癌的潜在治疗靶点。