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Abstract
Regulatory factor X-5 (RFX5) represents a key transcription regulator of MHCII gene expression in the immune system. This study aims to explore the molecular mechanisms and biological significance of RFX5. Firstly, by analyzing ENCODE chromatin immunoprecipitation (ChIP)-seq in HepG2 and TCGA RNA-seq data, we discovered lysine-specific demethylase 4A (KDM4A), also named JMJD2A, to be a major downstream target gene of RFX5. Moreover, RFX5 was verified to bind directly to the KDM4A’s promoter region and sequentially promoted its transcription determined by the ChIP-PCR assay and luciferase assay. In addition, RFX5-dependent regulation of KDM4A was demonstrated in HCC. Compared with adjacent non-tumor tissues, the expression levels of KDM4A were significantly raised in HCC tumor tissues. Notably, elevated levels of KDM4A were strongly correlated with HCC patient prognosis. Functionally, KDM4A overexpression largely rescued the growth inhibitory effects of RFX5 deletion, highlighting KDM4A as a downstream effector of RFX5. Mechanistically, the RFX5-KDM4A pathway promoted the progression of the cell cycle from G0/G1 to S phase and was protective against cell apoptosis through regulation of p53 and its downstream genes in HCC. In conclusion, RFX5 could promote HCC progression via transcriptionally activating KDM4A expression.
Highlights
Regulatory factor X-5 (RFX5) represents a key transcription regulator of MHCII gene expression in the immune system
Through systematic identification of RFX5’s transcriptional target genes determined by analyzing RNA Sequencing (RNA-seq) data from the the Cancer Genome Atlas (TCGA) Liver hepatocellular carcinoma (LIHC) dataset, this study reveals that RFX5 might be involved in repair of DNA damage, progression of the cell cycle and proliferation pathways
By analyzing the TCGA LIHC dataset, the RFX5 mRNA expression was significantly associated with the prognosis of patients with advanced Hepatocellular carcinoma (HCC) (Fig. 1B)
Summary
Regulatory factor X-5 (RFX5) represents a key transcription regulator of MHCII gene expression in the immune system. RFX5 overexpression in HCC cell lines and tumor tissues failed to provoke a tangible response in MHCII expression, suggesting that other, non-MHCII target genes may be involved in HCC p rogression[10]. Through systematic identification of RFX5’s transcriptional target genes determined by analyzing RNA-seq data from the TCGA LIHC dataset, this study reveals that RFX5 might be involved in repair of DNA damage, progression of the cell cycle and proliferation pathways. Though YWHAQ appeared to be the downstream target of RFX5, overexpression YWHAQ only partly reversed the growth inhibitory effects mediated by RFX5 deletion in HepG2 cells. These findings implied that RFX5 might promote HCC progression by regulating other target genes, YWHAQ
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