Targeting Gli transcription activation by small molecule suppresses tumor growth

G Bosco-Clément; F Zhang; Z Chen; H-M Zhou; H Li; I Mikami; T Hirata; A Yagui-Beltran; N Lui; H T Do; T Cheng; H-H Tseng; H Choi; L-T Fang; I-J Kim; D Yue; C Wang; Q Zheng; N Fujii; M Mann; D M Jablons; B He

doi:10.1038/onc.2013.164

Targeting Gli transcription activation by small molecule suppresses tumor growth

Oncogene. 2014 Apr 17;33(16):2087-97. doi: 10.1038/onc.2013.164. Epub 2013 May 20.

Authors

G Bosco-Clément¹, F Zhang², Z Chen³, H-M Zhou⁴, H Li¹, I Mikami⁵, T Hirata⁵, A Yagui-Beltran¹, N Lui¹, H T Do¹, T Cheng¹, H-H Tseng¹, H Choi¹, L-T Fang¹, I-J Kim¹, D Yue⁶, C Wang⁷, Q Zheng⁸, N Fujii⁹, M Mann¹⁰, D M Jablons¹, B He¹

Affiliations

¹ Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
² 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.
³ 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.
⁴ School of Life Sciences, Tsinghua University, Beijing, China.
⁵ 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.
⁶ 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.
⁷ Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
⁸ 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.
⁹ Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁰ Division of Cardiothoracic Surgery, Department of Surgery, University of California, San Francisco, CA, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Female
HCT116 Cells
HEK293 Cells
HT29 Cells
Hedgehog Proteins / genetics
Hedgehog Proteins / metabolism
Humans
Immunoblotting
Mice
Mice, Nude
NIH 3T3 Cells
Neoplasms / genetics
Neoplasms / pathology
Neoplasms / prevention & control*
Oligonucleotide Array Sequence Analysis
Protein Binding / drug effects
Pyrazoles / chemistry
Pyrazoles / pharmacology
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
TATA-Binding Protein Associated Factors / genetics
TATA-Binding Protein Associated Factors / metabolism
Transcription Factor TFIID / genetics
Transcription Factor TFIID / metabolism
Transcription Factors / genetics*
Transcription Factors / metabolism
Transcriptional Activation / drug effects*
Transcriptome / drug effects
Tumor Burden / drug effects
Tumor Burden / genetics
Xenograft Model Antitumor Assays
Zinc Finger Protein GLI1

Substances

FN1-8 compound
GLI1 protein, human
Hedgehog Proteins
Pyrazoles
Small Molecule Libraries
TAF9 protein, human
TATA-Binding Protein Associated Factors
Transcription Factor TFIID
Transcription Factors
Zinc Finger Protein GLI1

Abstract

Publication types

MeSH terms

Substances

Grants and funding