J Clin Invest 2011;121:3159-3175. (Reprinted with permission.) Hepatocellular carcinoma (HCC) is the fifth most common cancer

worldwide. It is more prevalent in men than in women. Related to this, recent genetic studies have revealed a causal role for androgen receptor (AR) in hepatocarcinogenesis, but the underlying molecular mechanism remains unclear. Here, we used genome-wide location and functional analyses to identify a critical mediator of AR signaling—cell cycle–related kinase (CCRK)—that drives hepatocarcinogenesis via a signaling pathway dependent on β-catenin and T cell factor (TCF). Ligand-bound AR activated CCRK transcription and protein expression via direct binding Compound Library purchase to the androgen-responsive element of the CCRK promoter in human HCC cell lines. In vitro analyses showed that CCRK was critical in

human cell lines for AR-induced cell cycle progression, hepatocellular proliferation, and malignant transformation. Ectopic expression of LEE011 cell line CCRK in immortalized human liver cells activated β-catenin/TCF signaling to stimulate cell cycle progression and to induce tumor formation, as shown in both xenograft and orthotopic models. Conversely, knockdown of CCRK decreased HCC cell growth, and this could be rescued by constitutively active β-catenin or TCF. In primary human HCC tissue samples, AR, CCRK, and β-catenin were concordantly overexpressed in the tumor cells. Furthermore, CCRK overexpression correlated with the tumor staging and poor overall survival of patients. Our results reveal a direct AR transcriptional target, CCRK, that promotes hepatocarcinogenesis through the upregulation of β-catenin/TCF signaling. Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third cause of cancer-related death worldwide. HCC usually occurs in the setting of chronic liver disease due to hepatitis of various etiologies. Men are at higher MCE risk of developing HCC, and the role of male sex hormones as tumor promoters is highly relevant. 1 The androgen receptor (AR) is critical for the development and maintenance of the male sexual phenotype. 2 AR is a type of nuclear

receptor that regulates gene transcription when activated by androgens. Upon activation, AR translocates to the nucleus, binds to androgen response elements (AREs) on target genes, and engages in crosstalk with transcription factors to eventually induce transcription of certain genes. Overexpression of AR has been reported in 60%-80% of human HCCs, 3 making it a formidable player in male HCC. In addition, liver-specific deletion of AR was shown to significantly reduce tumorigenicity in both carcinogen-induced and hepatitis B virus (HBV)-induced HCC mouse models. 4, 5 The mechanism of AR in HCC had remained unclear until a recent study established a novel means of crosstalk through cell cycle–related kinase (CCRK) to the Wnt/β-catenin signaling pathway, another important oncogenic pathway in HCC.