Survival factor NFIL3 restricts FOXO-induced gene expression in cancer (original) (raw)

  1. Maira M. Pires1,2,3,
  2. Sarah Mense3,
  3. Celine Lefebvre1,2,4,
  4. Boyi Gan5,
  5. Karen Justiano1,2,
  6. Ying-Ka Ingar Lau1,2,
  7. Ben Hopkins1,2,
  8. Cindy Hodakoski1,2,3,
  9. Susan Koujak1,2,
  10. Joseph Toole1,2,
  11. Franklyn Fenton1,2,
  12. Ashley Calahan1,2,
  13. Andrea Califano1,2,4,
  14. Ronald A. DePinho6,
  15. Matt Maurer1,2,7 and
  16. Ramon Parsons3,8
  17. 1Institute for Cancer Genetics,
  18. 2Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA;
  19. 3Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;
  20. 4Department of Biomedical Informatics, Columbia University, New York, New York, 10032, USA;
  21. 5Department of Experimental Radiation Oncology,
  22. 6Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  23. 7Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA

Abstract

Depending on the circumstance, FOXO (Forkhead O) (FOXO1, FOXO3, and FOXO4) transcription factors activate the expression of markedly different sets of genes to produce different phenotypic effects. For example, distinct FOXO-regulated transcriptional programs stimulate cell death or enhance organism life span. To gain insight into how FOXOs select specific genes for regulation, we performed a screen for genes that modify FOXO activation of TRAIL, a death receptor ligand capable of inducing extrinsic apoptosis. We discovered that the bZIP transcriptional repressor NFIL3 (nuclear factor interleukin 3-regulated) hindered FOXO transcription factor access to chromatin at the TRAIL promoter by binding to nearby DNA and recruiting histone deacetylase-2 (HDAC2) to reduce histone acetylation. In the same manner, NFIL3 repressed expression of certain FOXO targets—e.g., FAS, GADD45α (growth arrest and DNA damage-inducible, α), and _GADD45β—_but not others. NFIL3, which we found to be overexpressed in different cancers, supported tumor cell survival largely through repression of TRAIL and antagonized hydrogen peroxide-induced cell death. Moreover, its expression in cancer was associated with lower patient survival. Therefore, NFIL3 alters cancer cell behavior and FOXO function by acting on chromatin to restrict the menu of FOXO target genes. Targeting of NFIL3 could be of therapeutic benefit for cancer patients.

Footnotes