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 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.

[1]  I. Cowell.  E4BP4/NFIL3, a PAR‐related bZIP factor with many roles , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[2]  Van,et al.  A gene-expression signature as a predictor of survival in breast cancer. , 2002, The New England journal of medicine.

[3]  J. J. Chen,et al.  Profiling the downstream genes of tumor suppressor PTEN in lung cancer cells by complementary DNA microarray. , 2000, American journal of respiratory cell and molecular biology.

[4]  Yudong D. He,et al.  A Gene-Expression Signature as a Predictor of Survival in Breast Cancer , 2002 .

[5]  F. Christians,et al.  PTEN Expression Causes Feedback Upregulation of Insulin Receptor Substrate 2 , 2001, Molecular and Cellular Biology.

[6]  Mark Coles,et al.  The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development , 2009, Nature Immunology.

[7]  Rakesh Nagarajan,et al.  FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression , 2002, The Journal of Biological Chemistry.

[8]  E. Bertolino,et al.  A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation , 2012, Nature Immunology.

[9]  Lara J. Monteiro,et al.  Constitutively Nuclear FOXO3a Localization Predicts Poor Survival and Promotes Akt Phosphorylation in Breast Cancer , 2010, PloS one.

[10]  Jolyon Terragni,et al.  Phosphatidylinositol 3-kinase signaling in proliferating cells maintains an anti-apoptotic transcriptional program mediated by inhibition of FOXO and non-canonical activation of NFκB transcription factors , 2008, BMC Cell Biology.

[11]  W. Sellers,et al.  A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. , 2002, Cancer cell.

[12]  A. Kretsovali,et al.  Coordinated changes of histone modifications and HDAC mobilization regulate the induction of MHC class II genes by Trichostatin A , 2006, Nucleic acids research.

[13]  T. Tuschl,et al.  FOXO1 is an essential regulator of pluripotency in human embryonic stem cells , 2011, Nature Cell Biology.

[14]  Hanina Hibshoosh,et al.  PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. , 2005, Cancer research.

[15]  Howard Y. Chang,et al.  Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  T. Tsunoda,et al.  Growth and gene expression profile analyses of endometrial cancer cells expressing exogenous PTEN. , 2001, Cancer research.

[17]  J L Cleveland,et al.  Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[19]  Yonghong Xiao,et al.  FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell Homeostasis , 2007, Cell.

[20]  August B. Smit,et al.  Genome-wide gene expression and promoter binding analysis identifies NFIL3 as a repressor of C/EBP target genes in neuronal outgrowth , 2011, Molecular and Cellular Neuroscience.

[21]  S. Minucci,et al.  Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer , 2006, Nature Reviews Cancer.

[22]  M. Wigler,et al.  Design of a retroviral-mediated ecdysone-inducible system and its application to the expression profiling of the PTEN tumor suppressor , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Sarat Chandarlapaty,et al.  AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. , 2011, Cancer cell.

[24]  T. Barrette,et al.  Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. , 2007, Neoplasia.

[25]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[26]  Wei He,et al.  A FoxO–Smad synexpression group in human keratinocytes , 2006, Proceedings of the National Academy of Sciences.

[27]  A. Brunet,et al.  The FoxO code , 2008, Oncogene.

[28]  S. Fröhling,et al.  AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias , 2011, Cell.

[29]  C. Glass,et al.  FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages , 2010, The EMBO journal.

[30]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[31]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[32]  A. Schröder,et al.  IL-4-induced transcription factor NFIL3/E4BP4 controls IgE class switching , 2009, Proceedings of the National Academy of Sciences.