title: Oncovirus Kaposi sarcoma herpesvirus (KSHV) represses tumor suppressor PDLIM2 to persistently activate nuclear factor κB (NF-κB) and STAT3 transcription factors for tumorigenesis and tumor maintenance.
abstract: Kaposi sarcoma herpesvirus (KSHV) is the most common cause of malignancies among AIDS patients. However, how KSHV induces tumorigenesis remains largely unknown. Here, we demonstrate that one important mechanism underlying the tumorigenesis of KSHV is through transcriptional repression of the tumor suppressor gene PDZ-LIM domain-containing protein 2 (PDLIM2). PDLIM2 expression is repressed in KSHV-transformed human umbilical vascular endothelial cells as well as in KSHV-associated cancer cell lines and primary tumors. Importantly, PDLIM2 repression is essential for KSHV-induced persistent activation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) and subsequent tumorigenesis and tumor maintenance. Our mechanistic studies indicate that PDLIM2 repression by KSHV involves DNA methylation. Notably, the epigenetic repression of PDLIM2 can be reversed by 5-aza-2-deoxycytidine and vitamin D to suppress KSHV-associated cancer cell growth. These studies not only improve our understanding of KSHV pathogenesis but also provide immediate therapeutic strategies for KSHV-mediated cancers, particularly those associated with AIDS.
authors: From the University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15232, and the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
authors: Fan
authors: F
authors: Sun
authors: From the University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15232, and.
authors: Yadong
authors: Y
authors: Xiao
authors: From the University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15232, and the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 quz@upmc.edu.
authors: Zhaoxia
authors: Z
authors: Qu
mesh_terms: D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D016147:Genes, Tumor Suppressor; D019288:Herpesvirus 8, Human / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D016328:NF-kappa B; C502929:PDLIM2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Cancer; HIV/AIDS-related Malignancies; KSHV/HHV8; NF-kappa B (NF-KB); PDLIM2; STAT3; Tumor Suppressor Gene; Tumor Virus