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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
FOXO transcription factors control E2F1 transcriptional specificity and apoptotic function
Igor Shats1, Michael L Gatza, Beiyu Liu
1Authors' Affiliations: Duke Institute for Genome Sciences and Policy, Department of Molecular Genetics and Microbiology, Duke University Medical Center; Department of Biomedical Engineering, Duke University, Durham, North Carolina.
Cancer Research
|August 23, 2013
Summary
The transcription factor E2F1 cooperates with FOXO factors to induce apoptosis. This E2F1/FOXO axis is often disrupted in cancer, but its reactivation via HDAC and PI3K inhibitors shows therapeutic promise.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Biology
Background:
- The transcription factor E2F1 regulates cell proliferation and apoptosis, but its precise molecular mechanisms are not fully understood.
- FOXO transcription factors play critical roles in cellular stress responses and apoptosis.
Purpose of the Study:
- To elucidate the molecular mechanisms by which E2F1 controls apoptosis.
- To investigate the role of FOXO transcription factors in E2F1-mediated apoptosis.
- To explore the therapeutic potential of targeting the E2F1/FOXO axis in cancer.
Main Methods:
- Identification of FOXO transcription factors as E2F1 target genes.
- Co-immunoprecipitation assays to detect E2F1/FOXO complex formation.
- RNA interference (RNAi) to assess the role of FOXO in E2F1 target gene regulation.
- Use of a constitutively active FOXO3 mutant to study the impact of survival signaling.
- Analysis of E2F1/FOXO transcriptional programs in cancer patient data.
- Treatment with histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) inhibitors.
Main Results:
- FOXO transcription factors form a feed-forward loop with E2F1 to enhance the induction of apoptotic genes.
- E2F1 forms a complex with FOXO1 and FOXO3, and FOXO is required for E2F1 binding to target gene promoters.
- A FOXO3 mutant resistant to survival kinase inactivation rescued E2F1-mediated transcription and apoptosis from growth factor inhibition.
- The E2F1/FOXO axis is frequently downregulated in various cancer types, correlating with poor prognosis.
- HDAC and PI3K inhibitors activate E2F1/FOXO transcription and E2F1-induced apoptosis in a FOXO3-dependent manner.
- Combination therapy with a histone deacetylase inhibitor (vorinostat) and a PI3K inhibitor enhanced FOXO-dependent apoptosis.
Conclusions:
- The E2F1/FOXO axis represents a critical regulatory mechanism controlling E2F1 apoptotic activity in response to survival signaling.
- Therapeutic reactivation of this tumor-suppressive pathway offers a potential broad-acting cancer therapy.
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