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Targeting Gli transcription activation by small molecule suppresses tumor growth
G Bosco-Clément1, F Zhang2, Z Chen3
1Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 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.
Insights
Researchers discovered a new molecule, FN1-8, that blocks Gli/TAF9 interactions, inhibiting cancer cell growth and tumor development. This finding offers a potential new strategy for anticancer drug development by targeting Gli transactivation.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hedgehog signaling pathway targeted at the cell membrane shows anticancer potential.
- Gli transcription factors are central to Hedgehog signaling but can be activated by other routes.
- Targeting Gli transactivation is a potential anticancer strategy.
Purpose of the Study:
- To identify novel interactions regulating Gli transactivation.
- To develop a small molecule inhibitor targeting Gli transactivation.
- To evaluate the anticancer efficacy of the novel inhibitor.
Main Methods:
- Identified and validated the interaction between Gli proteins and TBP-associated factor 9 (TAF9).
- Developed a synthetic small molecule, FN1-8, to disrupt the Gli/TAF9 interaction.
- Assessed FN1-8's effect on Gli/TAF9-dependent transcription, cancer cell proliferation (in vitro), and tumor growth (in vivo).
Main Results:
- A functional interaction between Gli proteins and TAF9 was identified.
- The novel small molecule FN1-8 effectively inhibits Gli/TAF9 interaction and downstream transcriptional activity.
- FN1-8 demonstrated suppression of cancer cell proliferation and inhibition of tumor growth in vivo.
Conclusions:
- Targeting the Gli/TAF9 interaction represents a novel approach to inhibit oncogenic pathways.
- FN1-8 is a promising therapeutic agent for cancer treatment by blocking Gli transactivation.
- Inhibition of Gli transactivation is a viable strategy for developing new anticancer therapies.
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