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Transcriptome Analysis of Signaling Pathways Targeted by Ellagic Acid in Hepatocellular Carcinoma Cells

ABSTRACT: Ellagic acid (EA) possesses prominent inhibitory activities against various cancers, including hepatocellular carcinoma (HCC). Recent study showing EA’s activities in suppressing HCC cell proliferation and tumor formation, we further demonstrate that EA reduces cell viability, and induces DNA damage and cell cycle arrest at G1 phase. Employing RNA-Seq, we identified 5765 differentially expressed genes (DEGs) encoding proteins with over 2.0-fold change in EA-treated HepG2 cells. Following Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the DEGs caused by EA treatment showed significant enrichment in pathways regulating DNA replication and cell cycle progression. Consistently, integrative analyses of this RNA-seq dataset with a TCGA-LIHC dataset derived from HCC patients confirmed these two pathways as EA’s primary targets. Furthermore, we identified p21 as a primary target gene of EA using the interaction network analysis of the DEGs regulating these pathways. Consistent with the results of our bioinformatic analyses, p21 knockdown desensitized four different liver cancer cell lines to EA treatment. Collectively, our study demonstrated that EA primarily targeted the G1/S phase checkpoint and DNA synthesis to inhibit HCC cell proliferation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171311 | GEO | 2021/04/02

REPOSITORIES: GEO

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Project description:Barr2017 - Dynamics of p21 in hTert-RPE1 cells This deteministic model reveals that a bistable switch created by Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, prevents premature S-phase exit upon DNA damage This model is described in the article: DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. Barr AR, Cooper S, Heldt FS, Butera F, Stoy H, Mansfeld J, Novák B, Bakal C. Nat Commun 2017 Mar; 8: 14728 Abstract: Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability. This model is hosted on BioModels Database and identified by: BIOMD0000000660. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Transcriptome Analysis of Signaling Pathways Targeted by Ellagic Acid in Hepatocellular Carcinoma Cells

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