title: Oncogenic potential of histone-variant H2A.Z.1 and its regulatory role in cell cycle and epithelial-mesenchymal transition in liver cancer.
abstract: H2A.Z is a highly conserved H2A variant, and two distinct H2A.Z isoforms, H2A.Z.1 and H2A.Z.2, have been identified as products of two non-allelic genes, H2AFZ and H2AFV. H2A.Z has been reported to be overexpressed in breast, prostate and bladder cancers, but most studies did not clearly distinguish between isoforms. One recent study reported a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. Here we first report that H2A.Z.1 plays a pivotal role in the liver tumorigenesis by selectively regulating key molecules in cell cycle and epithelial-mesenchymal transition (EMT). H2AFZ expression was significantly overexpressed in a large cohort of hepatocellular carcinoma (HCC) patients, and high expression of H2AFZ was significantly associated with their poor prognosis. H2A.Z.1 overexpression was demonstrated in a subset of human HCC and cell lines. H2A.Z.1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins and caused apoptotic cell death of HCC cells. We also observed that H2A.Z.1 knockdown reduced the metastatic potential of HCC cells by selectively modulating epithelial-mesenchymal transition regulatory proteins such as E-cadherin and fibronectin. In addition, H2A.Z.1 knockdown reduced the in vivo tumor growth rate in a mouse xenograft model. In conclusion, our findings suggest the oncogenic potential of H2A.Z.1 in liver tumorigenesis and that it plays established role in accelerating cell cycle transition and EMT during hepatocarcinogenesis. This makes H2A.Z.1 a promising target in liver cancer therapy.
authors: Laboratory of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.|Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors: Hee Doo
authors: HD
authors: Yang
authors: Department of Cardiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors: Pum-Joon
authors: PJ
authors: Kim
authors: Laboratory of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.|Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors: Jung Woo
authors: JW
authors: Eun
authors: Laboratory of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.|Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors: Qingyu
authors: Q
authors: Shen
authors: Laboratory of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.|Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors: Hyung Seok
authors: HS
authors: Kim
authors: Laboratory of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.|Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors: Woo Chan
authors: WC
authors: Shin
authors: Department of Kidney System, College of Oriental Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors: Young Min
authors: YM
authors: Ahn
authors: Laboratory of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors: Won Sang
authors: WS
authors: Park
authors: Laboratory of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors: Jung Young
authors: JY
authors: Lee
authors: Laboratory of Oncogenomics, Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.|Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.|Cancer Evolution Research Center, The Catholic University of Korea, Seoul 06591, Republic of Korea.
authors: Suk Woo
authors: SW
authors: Nam
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D056945:Hep G2 Cells; D064593:Heterografts; D006657:Histones / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014162:Transfection
chemical_list: D006657:Histones; C077020:histone H2A.F-Z
keywords: H2A.Z.1; cell cycle; epithelial-mesenchymal transition; liver cancer