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组蛋白去甲基酶 JMJD2D 通过增强 EpCAM 和 Sox9 的表达促进肝癌干细胞样细胞的自我更新。

Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression.

机构信息

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China.

Department of Hepatobiliary Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, China.

出版信息

J Biol Chem. 2021 Jan-Jun;296:100121. doi: 10.1074/jbc.RA120.015335. Epub 2020 Dec 3.

DOI:10.1074/jbc.RA120.015335
PMID:33434575
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7948496/
Abstract

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.

摘要

癌症干细胞样细胞 (CSCs) 导致肿瘤异质性、转移、治疗耐药性和复发率高。组蛋白赖氨酸去甲基酶 4D (KDM4D 或 JMJD2D) 在结肠癌和肝癌中高表达，促进癌症进展；然而，JMJD2D 在 CSCs 中的作用尚不清楚。在这里，我们表明 JMJD2D 在肝癌干细胞样细胞 (LCSCs) 中表达增加；JMJD2D 的下调抑制了 LCSCs 在体外和体内的自我更新，并通过减少循环 LCSCs 的存活和早期肺部定植来抑制 LCSCs 的肺转移。在机制上，JMJD2D 通过增强 CSC 标志物 EpCAM 和 Sox9 的表达促进 LCSC 自我更新；JMJD2D 通过与 β-连环蛋白/TCF4 和 Notch1 细胞内域分别相互作用降低 EpCAM 和 Sox9 启动子上的 H3K9me3 水平，从而增强其转录。在 JMJD2D 敲低的肝癌细胞中恢复 EpCAM 和 Sox9 的表达挽救了 LCSCs 的自我更新。使用 5-c-8HQ 抑制 JMJD2D 的药理作用降低了 LCSCs 的自我更新和肝癌的进展。总之，我们的研究结果表明，JMJD2D 通过增强 Wnt/β-连环蛋白和 Notch 信号通路中的 EpCAM 和 Sox9 表达促进 LCSC 自我更新，是肝癌的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/118c952baf20/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/7032bb6ffd62/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/8df3dc858865/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/452faf3f3999/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/b7694e5e7c2f/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/037b593b0a77/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/035d0b679f7d/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/118c952baf20/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/7032bb6ffd62/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/8df3dc858865/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/452faf3f3999/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/b7694e5e7c2f/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/037b593b0a77/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/035d0b679f7d/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5178/7948496/118c952baf20/gr7.jpg

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