Vaccinia-related kinase 1 promotes hepatocellular carcinoma by controlling the levels of cell cycle regulators associated with G1/S transition

// Namgyu Lee 1 , Jung-Hee Kwon 2 , Young Bae Kim 4 , Seong-Hoon Kim 1 , Sung Jin Park 1 , Weiguang Xu 3 , Hoe-Yune Jung 5 , Kyong-Tai Kim 1, 5 , Hee Jung Wang 3 , Kwan Yong Choi 1, 5 1 Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea 2 Cbs Bioscience Inc., Daejeon, Korea 3 Department of Surgery, Ajou University School of Medicine, Suwon, Korea 4 Department of Pathology, Ajou University School of Medicine, Suwon, Korea 5 Department of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea Correspondence to: Kwan Yong Choi, e-mail: kchoi@postech.ac.kr Keywords: HCC, VRK1, proliferation, cell cycle, luteolin Received: January 17, 2015      Accepted: August 24, 2015      Published: September 07, 2015 ABSTRACT We identified the specific role of vaccinia-related kinase 1 (VRK1) in the progression of hepatocellular carcinoma (HCC) and evaluated its therapeutic and prognostic potential. VRK1 levels were significantly higher in HCC cell lines than a normal hepatic cell line, and were higher in HCC than non-tumor tissue. VRK1 knockdown inhibited the proliferation of SK-Hep1, SH-J1 and Hep3B cells; moreover, depletion of VRK1 suppressed HCC tumor growth in vivo . We also showed that VRK1 knockdown increased the number of G1 arrested cells by decreasing cyclin D1 and p-Rb while upregulating p21 and p27, and that VRK1 depletion downregulated phosphorylation of CREB, a transcription factor regulating CCND1. Additionally, we found that luteolin, a VRK1 inhibitor, suppressed HCC growth in vitro and in vivo , and that the aberrant VRK1 expression correlated with poor prognostic features of HCC. High levels of VRK1 were associated with shorter overall and disease-free survival and higher recurrence rates. Taken together, our findings suggest VRK1 may act as a tumor promoter by controlling the level of cell cycle regulators associated with G1/S transition and could potentially serve as a therapeutic target and/or prognostic biomarker for HCC.