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ATP-dependent RNA helicase DDX3X, also known as DEAD (Asp-Glu-Ala-Asp) Box Polypeptide 3, X-Linked (DDX3X), is critical for RNA metabolism, and emerging evidence implicates ATP-dependent RNA helicase DDX3X’s participation in various cellular processes to modulate cancer progression. In this study, the clinical significance of <i>DDX3X</i> was addressed, and <i>DDX3X</i> was identified as a biomarker for poor prognosis. An exploration of transcriptomic data from 373 liver cancer patients from The Cancer Genome Atlas (TCGA) using Ingenuity Pathway Analysis (IPA) suggested an association between <i>DDX3X</i> expression and cancer metastasis. Lentiviral-based silencing of <i>DDX3X</i> in a hepatocellular carcinoma (HCC) cell line resulted in the suppression of cell migration and invasion. The molecular mechanism regarding ATP-dependent RNA helicase DDX3X in liver cancer progression had been addressed in many studies. I focused on the biological application of the <i>DDX3X</i>-mediated gene expression signature in cancer therapeutics. An investigation of the <i>DDX3X</i>-correlated expression signature via the L1000 platform of Connectivity Map (BROAD Institute) first identified a histone methyltransferase inhibitor, chaetocin, as a novel compound for alleviating metastasis in HCC. In this study, the prognostic value of <i>DDX3X</i> and the antimetastatic property of chaetocin are presented to shed light on the development of anti-liver cancer strategies.