Histone Demethylase JMJD2D Promotes Stemness Of Liver Cancer Stem Cells Through Wnt And Notch Signaling Pathway

Liver cancer is one of the most common cancers worldwide and represents the fourth most commonly diagnosed cancer and the second most common cancer-related cause of death in china,with most cases being diagnosed at an advanced stage.In the past few decades,we have made a great breakthrough in understanding the tumorgensis and progression of liver,but we are poorly understood.Liver cancer stem cells(LCSCs)contributes to high rate of heterogeneity,metastasis,therapeutic resistance and tumor recurrence resulting in poor outcome and limited therapeutic options.There are many cancer stem cell related biomarker such as CD 13,CD44,CD90,CD 133,OV6,EpCAM,Sox9.Many signaling pathways involve in cancer stem cell stemness maintenance.such as Wnt/β-catenin,Notch pathways,Hippo pathway.Histone demethylase is histone modification enzyme which participates in physiology,homeostasis and tumorigenesis process.JMJD2D(also called KDM4D)belongs to JMJD2 family which can remove the methyl on H3K9me2/3.JMJD2A,JMJD2B,JMJD2C and JMJD2D ware reported to promote the initiation and progression multiple types of cancer.In present study,we want to investigate the role of JMJD2D in liver cancer stem cells(LCSCs)stemness maintenance.Here,we found that JMJD2D is overexpressed in LCSCs and correlates with poor prognosis.Depletion of JMJD2D inhibits the initiation and proliferation of LCSCs in vitro and in vivo.JMJD2D promotes Wnt target gene EpCAM and Notch target gene Sox9 expression through interacting with β-catenin/TCF4 and NICD to reduce H3K9me3 levels at the promoter respectively.Finally,The JMJD2D inhibitor 5-c-8HQ can attenuate the stemness of LCSCs and shows no cytotoxicity to normal tissue.Collectively,our findings suggesting that JMJD2D is essential for LCSCs stemness maintenance,and JMJD2D could be a possible therapeutic target against LCSCs.