An E2F1/DDX11/EZH2 Positive Feedback Loop Promotes Cell Proliferation in Hepatocellular Carcinoma

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.

Downregulation of cell division cycle-associated protein 7 (CDCA7) suppresses cell proliferation, arrests cell cycle of ovarian cancer, and restrains angiogenesis by modulating enhancer of zeste homolog 2 (EZH2) expression

“…As an important component of polycomb group proteins (PcGs), EZH2 has been confirmed to be overexpressed in a variety of cancer types with lethal outcomes, including OC cases [ 13 , 14 ]. The EZH2 gene mainly contributes to tumor development by promoting angiogenesis, silencing tumor suppressor genes and inhibiting the apoptosis of tumor cells [ 22 , 23 ]. In addition, it has been widely demonstrated that EZH2 is closely associated with OC progression, invasion and metastasis [ 24 , 25 ].…”

Identification of Prognosis-Related Oxidative Stress Model with Immunosuppression in HCC

“…Research has also reported that decreased levels of CYP2C9 in HCC tissues [ 50 , 51 ], indicating the involvement of CYP2C9 in detoxification, may play an important role in the initiation of HCC. There is evidence that EZH2 is elevated in HCC and promotes proliferation, migration, and invasion of HCC cells, acted as a negative prognostic biomarker associated with immunosuppression, and is associated with sorafenib resistance in HCC [ 52 , 53 , 54 , 55 ]. SRXN1 , an antioxidant molecule, was significantly upregulated in HCC and its increasement might lessen BTG2 expression, resulting in an increase in HCC cell proliferation.…”

The DEAD/DEAH Box Helicase, DDX11, Is Essential for the Survival of Advanced Clear Cell Renal Cell Carcinoma and Is a Determinant of PARP Inhibitor Sensitivity

“…Besides melanoma and lung cancer, associations with hepatocellular carcinoma (HCC) and osteosarcoma have been reported [ 22 ]. Two recent studies have reported the association of DDX11 in HCC development and progression [ 29 , 30 ]. Yu et al suggested a pro-tumorigenic role of DDX11 in xenograft cancer animal models and demonstrated that DDX11 overexpression leads to activation of PI3K/AKT/mTOR signaling pathway [ 29 ].…”