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Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma.

ABSTRACT: Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates liver cancer cell proliferation. Mechanistically, liver-TEs are predominantly occupied by the histone demethylase, KDM1A. KDM1A negatively influences the methylation of histone H3 Lys4 (H3K4) of liver-TEs, resulting in the epigenetic silencing of HNF4A expression. The suppression of HNF4A mediated by KDM1A promotes liver cancer cell proliferation. In conclusion, this study uncovers a liver-TE/KDM1A/HNF4A regulatory axis that promotes liver cancer growth and highlights KDM1A as a promising therapeutic target. Our findings provide insight into the transposable element-related molecular mechanisms underlying liver cancer progression.

SUBMITTER: Jing T

PROVIDER: S-EPMC11224304 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma.

Jing Tiantian T Wei Dianhui D Xu Xiaoli X Wu Chengsi C Yuan Lili L Huang Yiwen Y Liu Yizhen Y Jiang Yanyi Y Wang Boshi B

Nature communications 20240704 1

Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regu ...[more]

PMID: 38965210

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Project description:BackgroundChronic alcohol consumption is more frequently associated with advanced, aggressive hepatocellular carcinoma (HCC) tumors. Alcohol adversely impacts ER/Golgi membrane trafficking and Golgi protein N-glycosylation in hepatocytes; these effects have been attributed (in part) to dysregulated adenosine diphosphate-ribosylation factor (ARF) GTPase signaling. Here, we investigated the role of the ARF GTPase guanine exchange factor PSD4 in HCC progression.MethodsR-based bioinformatics analysis was performed on publicly available array data. Modulating gene expression was accomplished via lentiviral vectors. Gene expression was analyzed using quantitative real-time PCR and immunoblotting. PSD4 promoter methylation was assessed using quantitative methylation-specific PCR. Phospho-p65(S276)/DNMT1 binding to the PSD4 promoter was analyzed via chromatin immunoprecipitation. We constructed ethanol/DEN-induced and DEN only-induced transgenic murine models of HCC.ResultsWe identified PSD4 as a hypermethylated, suppressed gene in alcohol-related HCC tumors; however, PSD4 was not dysregulated in all-cause HCC tumors. Certain HCC cell lines also displayed varying degrees of PSD4 downregulation. PSD4 overexpression or knockdown decreased and increased cell migration and invasiveness, respectively. Mechanistically, PSD4 transcription was repressed by TNF-α-induced phospho-p65(S276)'s recruitment of DNA methyltransferase 1 (DNMT1), resulting in PSD4 promoter methylation. PSD4 inhibited pro-EMT CDC42 activity, resulting in downregulation of E-cadherin and upregulation of N-cadherin and vimentin. Hepatocyte-specific PSD4 overexpression reduced ethanol/DEN-induced HCC tumor progression and EMT marker expression in vivo.ConclusionsPSD4 is a hypermethylated, suppressed gene in alcohol-related HCC tumors that negatively modulated pro-EMT CDC42 activity. Furthermore, we present a novel phospho-NF-κB p65(S276)/DNMT1-mediated promoter methylation mechanism by which TNF-α/NF-κB signaling represses PSD4 transcription in HCC cells.

Project description:Histone lysine demethylase LSD1, also known as KDM1A, has been found to regulate multiple cancer hallmarks since it was first identified in 2004. Recently, it has emerged as a promising target for stimulating anti-tumor immunity, specifically boosting T cell activity. However, it remains unclear whether and how it remodels the tumor microenvironment to drive oncogenic processes in esophageal squamous cell carcinoma (ESCC). In this study, protein levels in ESCC tissues were evaluated by immunostaining of tissue microarrays. Cell growth was assessed by colony formation assays in vitro and subcutaneous xenograft models in vivo. High-throughput transcriptomics and spatial immune proteomics were performed using bulk RNA sequencing and digital spatial profiling techniques, respectively. Epigenetic regulation of RAD51 by methylated histone proteins was analyzed using chromatin immunoprecipitated quantitative PCR assays. Finally, our clinical data indicate that KDM1A precisely predicts the overall survival of patients with early-stage ESCC. Inhibition of KDM1A blocked the growth of ESCC cells in vitro and in vivo. Mechanistically, our transcriptomics and spatial immune proteomics data, together with rescue assays, demonstrated that KDM1A specifically removes methyl residues from the histone protein H3K9me2, a transcription repressive marker, thus reducing its enrichment at the promoter of RAD51 to epigenetically reactivate its transcription. Additionally, it significantly inhibits the expression of NF-κB signaling-dependent proinflammatory genes IL-6 and IL-1B through RAD51, thus blocking the STING-associated anti-tumor immunity in stromal tumor-infiltrating lymphocytes (sTIL). Overall, our findings not only indicate that KDM1A is a promising target for ESCC patients at early stages but also provide novel mechanistic insights into its spatial regulation of STING-associated anti-tumor immunity in sTILs to drive the oncogenic processes in ESCC. The translation of these findings will ultimately guide more appropriate combinations of spatial immunotherapies with KDM1A inhibitors to improve the overall survival of specific subgroups in ESCC.

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Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma.

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Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma.

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