title: Loss of IGFBP7 expression and persistent AKT activation contribute to SMARCB1/Snf5-mediated tumorigenesis.
abstract: SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in malignant rhabdoid tumors (MRT) and atypical teratoid/rhabdoid tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. SMARCB1 is a core subunit of Swi/Snf chromatin remodeling complexes, and loss of SMARCB1 or other subunits of these complexes has been observed in a variety of tumor types. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors, which developed in Smarcb1 heterozygous p53(-/-) mice. We find that while re-introduction of Smarcb1 does not induce growth arrest, it restores sensitivity to programmed cell death and completely abolishes the ability of the tumor cells to grow as xenografts. We describe persistent activation of AKT signaling in Smarcb1-deficient cells, which stems from PI3K (phosphatidylinositol 3'-kinase)-mediated signaling and which contributes to the survival and proliferation of the tumor cells. We further demonstrate that inhibition of AKT is effective in preventing proliferation of Smarcb1-deficient cells in vitro and inhibits the development of xenografted tumors in vivo. Profiling Smarcb1-dependent gene expression, we find genes that require Smarcb1 and Swi/Snf for their expression to be enriched for extracellular matrix and cell adhesion functions. We find that Smarcb1 is required for transcriptional activation of Igfbp7, a member of the insulin-like growth factor-binding proteins family and a tumor suppressor in itself, and show that re-introduction of Igfbp7 alone can hinder tumor development. Our results define a novel mechanism for Smarcb1-mediated tumorigenesis and highlight potential therapeutic targets.
authors.affiliation: Department of Cell and Developmental Biology, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Darr
authors.affiliation: Department of Cell and Developmental Biology, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Klochendler
authors.affiliation: Department of Cell and Developmental Biology, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Isaac
authors.affiliation: Department of Cell and Developmental Biology, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Eden
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018335:Rhabdoid Tumor / Q000235:genetics / Q000378:metabolism*; D000071796:SMARCB1 Protein; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D018969:Insulin-Like Growth Factor Binding Proteins; D000071796:SMARCB1 Protein; C513265:Smarcb1 protein, mouse; D016159:Tumor Suppressor Protein p53; C102529:insulin-like growth factor binding protein-related protein 1; D051057:Proto-Oncogene Proteins c-akt