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

Targeting Gli transcription activation by small molecule suppresses tumor growth.

Author information

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.

PMID:
23686308
PMCID:
PMC3947751
DOI:
10.1038/onc.2013.164
[Indexed for MEDLINE]
Free PMC Article
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