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FOXO transcription factors control E2F1 transcriptional specificity and apoptotic function.

Publication ,  Journal Article
Shats, I; Gatza, ML; Liu, B; Angus, SP; You, L; Nevins, JR
Published in: Cancer research
October 2013

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.

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Published In

Cancer research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

October 2013

Volume

73

Issue

19

Start / End Page

6056 / 6067

Related Subject Headings

  • Vorinostat
  • Tumor Cells, Cultured
  • Survival Rate
  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Real-Time Polymerase Chain Reaction
  • RNA, Small Interfering
  • RNA, Messenger
  • Proto-Oncogene Proteins c-akt
  • Promoter Regions, Genetic
 

Citation

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Shats, I., Gatza, M. L., Liu, B., Angus, S. P., You, L., & Nevins, J. R. (2013). FOXO transcription factors control E2F1 transcriptional specificity and apoptotic function. Cancer Research, 73(19), 6056–6067. https://doi.org/10.1158/0008-5472.can-13-0453
Shats, Igor, Michael L. Gatza, Beiyu Liu, Steven P. Angus, Lingchong You, and Joseph R. Nevins. “FOXO transcription factors control E2F1 transcriptional specificity and apoptotic function.Cancer Research 73, no. 19 (October 2013): 6056–67. https://doi.org/10.1158/0008-5472.can-13-0453.
Shats I, Gatza ML, Liu B, Angus SP, You L, Nevins JR. FOXO transcription factors control E2F1 transcriptional specificity and apoptotic function. Cancer research. 2013 Oct;73(19):6056–67.
Shats, Igor, et al. “FOXO transcription factors control E2F1 transcriptional specificity and apoptotic function.Cancer Research, vol. 73, no. 19, Oct. 2013, pp. 6056–67. Epmc, doi:10.1158/0008-5472.can-13-0453.
Shats I, Gatza ML, Liu B, Angus SP, You L, Nevins JR. FOXO transcription factors control E2F1 transcriptional specificity and apoptotic function. Cancer research. 2013 Oct;73(19):6056–6067.

Published In

Cancer research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

October 2013

Volume

73

Issue

19

Start / End Page

6056 / 6067

Related Subject Headings

  • Vorinostat
  • Tumor Cells, Cultured
  • Survival Rate
  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Real-Time Polymerase Chain Reaction
  • RNA, Small Interfering
  • RNA, Messenger
  • Proto-Oncogene Proteins c-akt
  • Promoter Regions, Genetic