title: RNA helicase DEAD box protein 5 regulates Polycomb repressive complex 2/Hox transcript antisense intergenic RNA function in hepatitis B virus infection and hepatocarcinogenesis.
abstract: Chronic hepatitis B virus (HBV) infection is a major factor in hepatocellular carcinoma (HCC) pathogenesis by a mechanism not yet understood. Elucidating mechanisms of HBV-mediated hepatocarcinogenesis is needed to gain insights into classification and treatment of HCC. In HBV replicating cells, including virus-associated HCCs, suppressor of zeste 12 homolog (SUZ12), a core subunit of Polycomb repressive complex2 (PRC2), undergoes proteasomal degradation. This process requires the long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR). Intriguingly, HOTAIR interacts with PRC2 and also binds RNA-binding E3 ligases, serving as a ubiquitination scaffold. Herein, we identified the RNA helicase, DEAD box protein 5 (DDX5), as a regulator of SUZ12 stability and PRC2-mediated gene repression, acting by regulating RNA-protein complexes formed with HOTAIR. Specifically, knockdown of DDX5 and/or HOTAIR enabled reexpression of PRC2-repressed genes epithelial cell adhesion molecule (EpCAM) and pluripotency genes. Also, knockdown of DDX5 enhanced transcription from the HBV minichromosome. The helicase activity of DDX5 stabilized SUZ12- and PRC2-mediated gene silencing, by displacing the RNA-binding E3 ligase, Mex-3 RNA-binding family member B (Mex3b), from HOTAIR. Conversely, ectopic expression of Mex3b ubiquitinated SUZ12, displaced DDX5 from HOTAIR, and induced SUZ12 down-regulation. In G2 phase of cells expressing the HBV X protein (HBx), SUZ12 preferentially associated with Mex3b, but not DDX5, resulting in de-repression of PRC2 targets, including EpCAM and pluripotency genes. Significantly, liver tumors from HBx/c-myc bitransgenic mice and chronically HBV-infected patients exhibited a strong negative correlation between DDX5 messenger RNA levels, pluripotency gene expression, and liver tumor differentiation. Notably, chronically infected HBV patients with HCC expressing reduced DDX5 exhibited poor prognosis after tumor resection, identifying DDX5 as an important player in poor prognosis HCC.
  
  
  
  The RNA helicase DDX5, and E3 ligase Mex3b, are important cellular targets for the design of novel, epigenetic therapies to combat HBV infection and poor prognosis HBV-associated liver cancer. (Hepatology 2016;64:1033-1048).
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN.|Purdue Center for Cancer Research, Purdue University, West Lafayette, IN.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Purdue Center for Cancer Research, Purdue University, West Lafayette, IN.|Department of Biochemistry, Purdue University, West Lafayette, IN.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xing
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN.|Purdue Center for Cancer Research, Purdue University, West Lafayette, IN.
authors.forename: Saravana Kumar Kailasam
authors.initials: SK
authors.lastname: Mani
authors.affiliation: Center for Cancer Research of Lyon, UMR INSERM 1052, CNRS 5286, Lyon Cedex 03, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bancel
authors.affiliation: Center for Cancer Research of Lyon, UMR INSERM 1052, CNRS 5286, Lyon Cedex 03, France.
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.affiliation: Center for Cancer Research of Lyon, UMR INSERM 1052, CNRS 5286, Lyon Cedex 03, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Purdue Center for Cancer Research, Purdue University, West Lafayette, IN.|Department of Biochemistry, Purdue University, West Lafayette, IN.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Tran
authors.affiliation: Center for Cancer Research of Lyon, UMR INSERM 1052, CNRS 5286, Lyon Cedex 03, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Merle
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN.|Purdue Center for Cancer Research, Purdue University, West Lafayette, IN.
authors.forename: Ourania
authors.initials: O
authors.lastname: Andrisani
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000209:etiology*; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000150:complications / Q000209:etiology*; D006801:Humans; D008113:Liver Neoplasms / Q000150:complications / Q000209:etiology*; D051379:Mice; D029543:Nucleocytoplasmic Transport Proteins / Q000502:physiology*; D063151:Polycomb Repressive Complex 2 / Q000502:physiology*; D062085:RNA, Long Noncoding / Q000502:physiology*
chemical_list: C000608169:HOTAIR long non-coding RNA, mouse; C561566:HOTAIR long untranslated RNA, human; D029543:Nucleocytoplasmic Transport Proteins; D062085:RNA, Long Noncoding; D063151:Polycomb Repressive Complex 2; C121148:DDX19B protein, human; C506751:Ddx5 protein, mouse; D053487:DEAD-box RNA Helicases