title: Targeting Gli transcription activation by small molecule suppresses tumor growth.
abstract: Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study, we identified an interaction between Gli proteins and a transcription coactivator TBP-associated factor 9 (TAF9), and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and downregulate Gli/TAF9-dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy.
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Bosco-Clément
authors.affiliation: 1] Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA [2] Tsinghua University Graduate School at Shenzhen, Division of Life and Health Sciences, Shenzhen, China.
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 1] Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA [2] School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: H-M
authors.initials: HM
authors.lastname: Zhou
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: 1] Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA [2] Department of Surgery, Division of Thoracic Surgery, Nippon Medical School, Tokyo, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Mikami
authors.affiliation: 1] Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA [2] Department of Surgery, Division of Thoracic Surgery, Nippon Medical School, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hirata
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Yagui-Beltran
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Lui
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: H T
authors.initials: HT
authors.lastname: Do
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: H-H
authors.initials: HH
authors.lastname: Tseng
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Choi
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: L-T
authors.initials: LT
authors.lastname: Fang
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: I-J
authors.initials: IJ
authors.lastname: Kim
authors.affiliation: 1] Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA [2] Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: D
authors.initials: D
authors.lastname: Yue
authors.affiliation: Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: 1] Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA [2] Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Thoracic Surgery II, Peking University Cancer Hospital and Institute, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Fujii
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of California, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mann
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Jablons
authors.affiliation: Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: He
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics / Q000378:metabolism; D035362:Transcription Factor TFIID / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D059467:Transcriptome / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
chemical_list: C000589025:FN1-8 compound; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D011720:Pyrazoles; D054852:Small Molecule Libraries; C106849:TAF9 protein, human; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1