title: KSHV-Mediated Regulation of Par3 and SNAIL Contributes to B-Cell Proliferation.
abstract: Studies have suggested that Epithelial-Mesenchymal Transition (EMT) and transformation is an important step in progression to cancer. Par3 (partitioning-defective protein) is a crucial factor in regulating epithelial cell polarity. However, the mechanism by which the latency associated nuclear antigen (LANA) encoded by Kaposi's Sarcoma associated herpesvirus (KSHV) regulates Par3 and EMTs markers (Epithelial-Mesenchymal Transition) during viral-mediated B-cell oncogenesis has not been fully explored. Moreover, several studies have demonstrated a crucial role for EMT markers during B-cell malignancies. In this study, we demonstrate that Par3 is significantly up-regulated in KSHV-infected primary B-cells. Further, Par3 interacted with LANA in KSHV positive and LANA expressing cells which led to translocation of Par3 from the cell periphery to a predominantly nuclear signal. Par3 knockdown led to reduced cell proliferation and increased apoptotic induction. Levels of SNAIL was elevated, and E-cadherin was reduced in the presence of LANA or Par3. Interestingly, KSHV infection in primary B-cells led to enhancement of SNAIL and down-regulation of E-cadherin in a temporal manner. Importantly, knockdown of SNAIL, a major EMT regulator, in KSHV cells resulted in reduced expression of LANA, Par3, and enhanced E-cadherin. Also, SNAIL bound to the promoter region of p21 and can regulate its activity. Further a SNAIL inhibitor diminished NF-kB signaling through upregulation of Caspase3 in KSHV positive cells in vitro. This was also supported by upregulation of SNAIL and Par3 in BC-3 transplanted NOD-SCID mice which has potential as a therapeutic target for KSHV-associated B-cell lymphomas.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Cancer, and Tumor Virology Program and Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hem C
authors.initials: HC
authors.lastname: Jha
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Cancer, and Tumor Virology Program and Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Cancer, and Tumor Virology Program and Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Upadhyay
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Cancer, and Tumor Virology Program and Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Darine W
authors.initials: DW
authors.lastname: El-Naccache
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Cancer, and Tumor Virology Program and Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Rajnish K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Cancer, and Tumor Virology Program and Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Sahu
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Cancer, and Tumor Virology Program and Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism; D001402:B-Lymphocytes / Q000821:virology*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002472:Cell Transformation, Viral / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology; D006566:Herpesviridae Infections / Q000378:metabolism*; D019288:Herpesvirus 8, Human; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000956:Antigens, Viral; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C509689:PARD3 protein, human; D000071250:Snail Family Transcription Factors; C109540:latency-associated nuclear antigen