Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.
Genes Dev. 2013 Apr 15;27(8):916-27. doi: 10.1101/gad.214049.113.
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.
根据具体情况，叉头框转录因子（FOXO）（FOXO1、FOXO3 和 FOXO4）激活了截然不同的基因表达谱，从而产生不同的表型效应。例如，不同的 FOXO 调控的转录程序会刺激细胞死亡或增强生物体寿命。为了深入了解 FOXO 如何选择特定的基因进行调控，我们进行了一项筛选，寻找能够改变 FOXO 对 TRAIL（一种能够诱导外在细胞凋亡的死亡受体配体）激活的基因。我们发现，bZIP 转录因子 NFIL3（核因子白细胞介素 3 调节）通过与附近的 DNA 结合并募集组蛋白去乙酰化酶-2（HDAC2）来减少组蛋白乙酰化，从而阻碍 FOXO 转录因子在 TRAIL 启动子上接近染色质。同样，NFIL3 抑制了某些 FOXO 靶基因（如 FAS、GADD45α（生长停滞和 DNA 损伤诱导，α）和 GADD45β）的表达，但不抑制其他基因的表达。我们发现，NFIL3 在不同的癌症中过度表达，它通过抑制 TRAIL 来支持肿瘤细胞的存活，并拮抗过氧化氢诱导的细胞死亡。此外，其在癌症中的表达与患者较低的存活率相关。因此，NFIL3 通过作用于染色质来限制 FOXO 靶基因的选择，从而改变癌细胞的行为和 FOXO 功能。靶向 NFIL3 可能对癌症患者具有治疗益处。
