title: Staphylococcal Nuclease and Tudor Domain Containing 1 (SND1 Protein) Promotes Hepatocarcinogenesis by Inhibiting Monoglyceride Lipase (MGLL).
abstract: Staphylococcal nuclease and tudor domain containing 1 (SND1) is overexpressed in multiple cancers, including hepatocellular carcinoma (HCC), and functions as an oncogene. This study was carried out to identify novel SND1-interacting proteins to better understand its molecular mechanism of action. SND1-interacting proteins were identified by a modified yeast two-hybrid assay. Protein-protein interaction was confirmed by co-immunoprecipitation analysis. Monoglyceride lipase (MGLL) expression was analyzed by quantitative RT-PCR, Western blot, and immunohistochemistry. MGLL-overexpressing clones were analyzed for cell proliferation and cell cycle analysis and in vivo tumorigenesis in nude mice. MGLL was identified as an SND1-interacting protein. Interaction of SND1 with MGLL resulted in ubiquitination and proteosomal degradation of MGLL. MGLL expression was detected in normal human hepatocytes and mouse liver, although it was undetected in human HCC cell lines. An inverse correlation between SND1 and MGLL levels was identified in a human HCC tissue microarray as well as in the TCGA database. Forced overexpression of MGLL in human HCC cells resulted in marked inhibition in cell proliferation with a significant delay in cell cycle progression and a marked decrease in tumor growth in nude mouse xenograft assays. MGLL overexpression inhibited Akt activation that is independent of enzymatic activity of MGLL and overexpression of a constitutively active Akt rescued cells from inhibition of proliferation and restored normal cell cycle progression. This study unravels a novel mechanism of SND1 function and identifies MGLL as a unique tumor suppressor for HCC. MGLL might function as a homeostatic regulator of Akt restraining its activation.
authors.affiliation: From the Departments of Human and Molecular Genetics and.
authors.forename: Devaraja
authors.initials: D
authors.lastname: Rajasekaran
authors.affiliation: From the Departments of Human and Molecular Genetics and.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jariwala
authors.affiliation: From the Departments of Human and Molecular Genetics and.
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Mendoza
authors.affiliation: From the Departments of Human and Molecular Genetics and.
authors.forename: Chadia L
authors.initials: CL
authors.lastname: Robertson
authors.affiliation: From the Departments of Human and Molecular Genetics and.
authors.forename: Maaged A
authors.initials: MA
authors.lastname: Akiel
authors.affiliation: Biostatistics.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Dozmorov
authors.affiliation: From the Departments of Human and Molecular Genetics and Massey Cancer Center, and VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: From the Departments of Human and Molecular Genetics and Massey Cancer Center, and VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia 23298 devanand.sarkar@vcuhealth.org.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004720:Endonucleases; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D004720:Endonucleases; C095221:SND1 protein, human; D008994:Monoacylglycerol Lipases
keywords: Akt PKB; MGLL; SND1; cell proliferation; liver cancer; protein-protein interaction; tumor suppressor gene