title: Survival factor NFIL3 restricts FOXO-induced gene expression in cancer.
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.
authors: Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.
authors: Megan
authors: M
authors: Keniry
authors: Maira M
authors: MM
authors: Pires
authors: Sarah
authors: S
authors: Mense
authors: Celine
authors: C
authors: Lefebvre
authors: Boyi
authors: B
authors: Gan
authors: Karen
authors: K
authors: Justiano
authors: Ying-Ka Ingar
authors: YK
authors: Lau
authors: Ben
authors: B
authors: Hopkins
authors: Cindy
authors: C
authors: Hodakoski
authors: Susan
authors: S
authors: Koujak
authors: Joseph
authors: J
authors: Toole
authors: Franklyn
authors: F
authors: Fenton
authors: Ashley
authors: A
authors: Calahan
authors: Andrea
authors: A
authors: Califano
authors: Ronald A
authors: RA
authors: DePinho
authors: Matt
authors: M
authors: Maurer
authors: Ramon
authors: R
authors: Parsons
mesh_terms: D017209:Apoptosis / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000175:diagnosis / Q000503:physiopathology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D002843:Chromatin; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C497440:NFIL3 protein, human; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D006655:Histone Deacetylases
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