Abstract
The transcription factor E2F1 is a key regulator of proliferation and apoptosis but the molecular mechanisms that mediate these cell fate decisions remain unclear. Here, we identify FOXO transcription factors as E2F1 target genes that act in a feed-forward regulatory loop to reinforce gene induction of multiple apoptotic genes. We found that E2F1 forms a complex with FOXO1 and FOXO3. RNAi-mediated silencing of FOXO impaired E2F1 binding to the promoters of cooperative target genes. A FOXO3 mutant insensitive to inactivation by survival kinases rescued the inhibitory effect of growth factor signaling on E2F1-mediated transcription and apoptosis. The E2F1/FOXO axis is frequently blocked in cancer, as evidenced by the specific downregulation of the FOXO-dependent E2F1 transcriptional program in multiple cancer types and by the association of a reduced E2F1/FOXO transcriptional program with poor prognosis. HDAC and phosphoinositide 3-kinase (PI3K) inhibitors were identified as specific activators of E2F1/FOXO transcription, acting to enhance E2F1-induced apoptosis in a FOXO3-dependent manner. Notably, combining the histone deacetylase inhibitor vorinostat with a PI3K inhibitor led to enhanced FOXO-dependent apoptosis. Collectively, our results identify E2F1/FOXO cooperation as a regulatory mechanism that places E2F1 apoptotic activity under the control of survival signaling. Therapeutic reactivation of this tumor suppressive mechanism may offer a novel broad-acting therapy for cancer.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Apoptosis*
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Biomarkers, Tumor / genetics*
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Bone Neoplasms / genetics
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology
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Breast Neoplasms / genetics
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Breast Neoplasms / mortality*
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Breast Neoplasms / pathology
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Cell Proliferation
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Chromatin Immunoprecipitation
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Chromones / pharmacology
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E2F1 Transcription Factor / antagonists & inhibitors
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E2F1 Transcription Factor / genetics
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E2F1 Transcription Factor / metabolism*
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Enzyme Inhibitors / pharmacology
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Female
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Fluorescent Antibody Technique
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Forkhead Box Protein O3
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Forkhead Transcription Factors / antagonists & inhibitors
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Hydroxamic Acids / pharmacology
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Immunoenzyme Techniques
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Immunoprecipitation
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Lung Neoplasms / genetics
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Lung Neoplasms / mortality*
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Lung Neoplasms / pathology
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Morpholines / pharmacology
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Oligonucleotide Array Sequence Analysis
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Osteosarcoma / genetics
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Osteosarcoma / metabolism
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Osteosarcoma / pathology*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Prognosis
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Survival Rate
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Tumor Cells, Cultured
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Vorinostat
Substances
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Biomarkers, Tumor
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Chromones
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E2F1 Transcription Factor
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E2F1 protein, human
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Enzyme Inhibitors
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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RNA, Messenger
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RNA, Small Interfering
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Vorinostat
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Proto-Oncogene Proteins c-akt