Guo Jun-Cheng, Liu Zhuo, Yang Yi-Jun, Guo Min, Zhang Jian-Quan, Zheng Jin-Fang
Hainan General Hospital, Haikou, China.
Hainan Medical University of Hainan Hospital affiliated, Haikou, China.
J Cell Mol Med. 2021 Jul;25(13):5949-5962. doi: 10.1111/jcmm.16342. Epub 2021 Apr 7.
Histone methylation plays important roles in mediating the onset and progression of various cancers, and lysine-specific demethylase 5B (KDM5B), as a histone demethylase, is reported to be an oncogene in hepatocellular carcinoma (HCC). However, the mechanism underlying its tumorigenesis remains undefined. Hence, we explored the regulatory role of KDM5B in HCC cells, aiming to identify novel therapeutic targets for HCC. Gene Expression Omnibus database and StarBase were used to predict important regulatory pathways related to HCC. Then, the expression of KDM5B and microRNA-448 (miR-448) in HCC tissues was detected by RT-qPCR and Western blot analysis. The correlation between KDM5B and miR-448 expression was analysed by Pearson's correlation coefficient and ChIP experiments, and the targeting of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) by miR-448 was examined by luciferase assay. Additionally, the effect of KDM5B on the proliferation, migration, invasion and apoptosis as well as tumorigenicity of transfected cells was assessed using ectopic expression and depletion experiments. KDM5B was highly expressed in HCC cells and was inversely related to miR-448 expression. KDM5B demethylated H3K4me3 on the miR-448 promoter and thereby inhibited the expression of miR-448, which in turn targeted YTHDF3 and integrin subunit alpha 6 (ITGA6) to promote the malignant phenotype of HCC. Moreover, KDM5B accelerated HCC progression in nude mice via the miR-448/YTHDF3/ITGA6 axis. Our study uncovered that KDM5B regulates the YTHDF3/ITGA6 axis by inhibiting the expression of miR-448 to promote the occurrence of HCC.
组蛋白甲基化在介导各种癌症的发生和发展中起着重要作用，赖氨酸特异性去甲基化酶5B（KDM5B）作为一种组蛋白去甲基化酶，据报道是肝细胞癌（HCC）中的一种癌基因。然而，其肿瘤发生的潜在机制仍不明确。因此，我们探讨了KDM5B在肝癌细胞中的调控作用，旨在确定肝癌的新治疗靶点。利用基因表达综合数据库和StarBase预测与肝癌相关的重要调控通路。然后，通过RT-qPCR和蛋白质免疫印迹分析检测肝癌组织中KDM5B和微小RNA-448（miR-448）的表达。通过Pearson相关系数和染色质免疫沉淀实验分析KDM5B与miR-448表达之间的相关性，并通过荧光素酶测定法检测miR-448对YTH N6-甲基腺苷RNA结合蛋白3（YTHDF3）的靶向作用。此外，使用异位表达和缺失实验评估KDM5B对转染细胞的增殖、迁移、侵袭和凋亡以及致瘤性的影响。KDM5B在肝癌细胞中高表达，且与miR-448表达呈负相关。KDM5B使miR-448启动子上的H3K4me3去甲基化，从而抑制miR-448的表达，而miR-448反过来靶向YTHDF3和整合素亚基α6（ITGA6）以促进肝癌的恶性表型。此外，KDM5B通过miR-448/YTHDF3/ITGA6轴加速裸鼠肝癌的进展。我们的研究发现，KDM5B通过抑制miR-448的表达来调节YTHDF3/ITGA6轴，从而促进肝癌的发生。
