title: BIN1 tumor suppressor regulates Fas/Fas ligand-mediated apoptosis through c-FLIP in cutaneous T-cell lymphoma.
abstract: The bridging integrator 1 (BIN1) tumor suppressor encodes multiple alternatively spliced isoforms implicated in DNA repair, cell-cycle control, apoptosis and membrane dynamics. BIN1 attenuation has been reported in several solid tumors; however, the role of BIN1 in lymphomagenesis remains unexplored. We recently demonstrated that BIN1 transcript levels are significantly downregulated in CD4(+)CD7(-) Sezary cells from patients with Sezary syndrome (SS), a subtype of cutaneous T-cell lymphoma (CTCL). We have now demonstrated that restored BIN1 expression in CTCL cells leads to a significant reduction in cell proliferation, an increase in spontaneous and Fas/Fas ligand (Fas/FasL)-induced apoptosis in vitro and inhibition of tumorigenic activity of CTCL cells in vivo. Interestingly, restoration of BIN1 expression in CTCL cells downregulates the expression of c-FLIP, an important inhibitor of Fas/FasL-mediated apoptosis, and activates the caspase cascade; these phenotypes can be rescued by knockdown of BIN1. Importantly, significantly reduced BIN1 expression and increased c-FLIP expression are observed in primary CTCL patient samples, and high BIN1 and low c-FLIP mRNA levels correlate with better survival rate in SS patients. These results indicate that BIN1 regulates Fas/FasL-mediated apoptosis through c-FLIP and that BIN1 deficiency may have an important role in CTCL pathogenesis by causing apoptosis resistance. Thus BIN1 and c-FLIP represent potential therapeutic targets in CTCL.
authors.affiliation: 1] Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada [2] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Esmailzadeh
authors.affiliation: 1] Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada [2] Molecular Medicine Laboratory, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada [3] Chieng Genomics Center, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 1] Molecular Medicine Laboratory, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada [2] Chieng Genomics Center, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada.
authors.forename: M-W
authors.initials: MW
authors.lastname: Su
authors.affiliation: 1] Molecular Medicine Laboratory, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada [2] Chieng Genomics Center, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: 1] Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada [2] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002453:Cell Cycle; D049109:Cell Proliferation; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D019014:fas Receptor