Abstract
Hepatocellular carcinoma (HCC) accounts for one of the leading causes of cancer-related death, and is attributed to the dysregulation of genes involved in genome stability. DDX11, a DNA helicase, has been implicated in rare genetic disease and human cancers. Yet, its clinical value, biological function, and the underlying mechanism in HCC progression are not fully understood. Here, we show that DDX11 is upregulated in HCC and exhibits oncogenic activity via EZH2/p21 signaling. High expression of DDX11 is significantly correlated with poor outcomes of HCC patients in two independent cohorts. DDX11 overexpression increases HCC cell viabilities and colony formation, whereas DDX11 knockdown arrests cells at G1 phase without alteration of p53 expression. Ectopic expression of DDX11 reduces, while depletion of DDX11 induces the expression of p21. Treatment of p21 siRNA markedly attenuates the cell growth suppression caused by DDX11 silence. Further studies reveal that DDX11 interacts with EZH2 in HCC cells to protect it from ubiquitination-mediated protein degradation, consequently resulting in the downregulation of p21. In addition, E2F1 is identified as one of the upstream regulators of DDX11, and forms a positive feedback loop with EZH2 to upregulate DDX11 and facilitate cell proliferation. Collectively, our data suggest DDX11 as a promising prognostic factor and an oncogene in HCC via a E2F1/DDX11/EZH2 positive feedback loop.
Highlights
Hepatocellular carcinoma (HCC), accounting for the majority of primary liver cancer, is the second leading cause for cancer-related death in many parts of the world [1]
Using The Cancer Genome Atlas (TCGA) data, we firstly assessed the expression of DDX11 in TCGA gastrointestinal cancers, including liver hepatocellular carcinoma (LIHC), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), and stomach adenocarcinoma (STAD)
Analyses based on TCGA and Oncomine data validated the upregulation of DDX11 mRNA in HCC tissues
Summary
Hepatocellular carcinoma (HCC), accounting for the majority of primary liver cancer, is the second leading cause for cancer-related death in many parts of the world [1]. The global burden of HCC has been increasing for decades and the morbidity may soon surpass one million cases per year [2]. Over half of the patients with HCC were diagnosed at advanced-stage disease, and must receive. DDX11 Promotes HCC Growth via EZH2/p21 systemic treatments, to which rare significant progress has been made [3, 4]. The improvement of the prognosis of HCC patients is modest and limited. Genomic and transcriptomic studies provide novel insights into the biological mechanism of the development and progression of HCC [3, 4]. Further studies are required to identify potential prognostic and therapeutic biomarkers
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