Survival factor NFIL3 restricts FOXO-induced gene expression in cancer

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...

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Published in:	Genes & development Vol. 27; no. 8; pp. 916 - 927
Main Authors:	Keniry, Megan, Pires, Maira M, Mense, Sarah, Lefebvre, Celine, Gan, Boyi, Justiano, Karen, Lau, Ying-Ka Ingar, Hopkins, Ben, Hodakoski, Cindy, Koujak, Susan, Toole, Joseph, Fenton, Franklyn, Calahan, Ashley, Califano, Andrea, DePinho, Ronald A, Maurer, Matt, Parsons, Ramon
Format:	Journal Article
Language:	English
Published:	United States Cold Spring Harbor Laboratory Press 15-04-2013
Subjects:	Apoptosis - genetics Basic-Leucine Zipper Transcription Factors - genetics Basic-Leucine Zipper Transcription Factors - metabolism Binding Sites Breast Neoplasms - diagnosis Breast Neoplasms - physiopathology Cell Line, Tumor Chromatin - metabolism Forkhead Box Protein O1 Forkhead Transcription Factors - metabolism Gene Expression Regulation, Neoplastic HEK293 Cells Histone Deacetylases - metabolism Humans Kaplan-Meier Estimate Prognosis Promoter Regions, Genetic Protein Binding Research Paper RNA, Small Interfering - metabolism TNF-Related Apoptosis-Inducing Ligand - genetics
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0890-9369 1549-5477
DOI:	10.1101/gad.214049.113