Huot Geneviève, Vernier Mathieu, Bourdeau Véronique, Doucet Laurent, Saint-Germain Emmanuelle, Gaumont-Leclerc Marie-France, Moro Alejandro, Ferbeyre Gerardo
Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
Mol Biol Cell. 2014 Mar;25(5):554-65. doi: 10.1091/mbc.E13-02-0110. Epub 2014 Jan 8.
The expression of the forkhead transcription factor checkpoint suppressor 1 (CHES1), also known as FOXN3, is reduced in many types of cancers. We show here that CHES1 decreases protein synthesis and cell proliferation in tumor cell lines but not in normal fibroblasts. Conversely, short hairpin RNA-mediated depletion of CHES1 increases tumor cell proliferation. Growth suppression depends on the CHES1 forkhead DNA-binding domain and correlates with the nuclear localization of CHES1. CHES1 represses the expression of multiple genes, including the kinases PIM2 and DYRK3, which regulate protein biosynthesis, and a number of genes in cilium biogenesis. CHES1 binds directly to the promoter of PIM2, and in cells expressing CHES1 the levels of PIM2 are reduced, as well as the phosphorylation of the PIM2 target 4EBP1. Overexpression of PIM2 or eIF4E partially reverses the antiproliferative effect of CHES1, indicating that PIM2 and protein biosynthesis are important targets of the antiproliferative effect of CHES1. In several human hematopoietic cancers, CHES1 and PIM2 expressions are inversely correlated, suggesting that repression of PIM2 by CHES1 is clinically relevant.
叉头转录因子检查点抑制因子1（CHES1，也称为FOXN3）的表达在多种癌症中降低。我们在此表明，CHES1可降低肿瘤细胞系中的蛋白质合成和细胞增殖，但对正常成纤维细胞无此作用。相反，短发夹RNA介导的CHES1缺失会增加肿瘤细胞增殖。生长抑制取决于CHES1叉头DNA结合域，并与CHES1的核定位相关。CHES1可抑制多个基因的表达，包括调节蛋白质生物合成的激酶PIM2和DYRK3，以及一些参与纤毛生物发生的基因。CHES1直接结合PIM2的启动子，在表达CHES1的细胞中，PIM2的水平降低，PIM2靶标4EBP1的磷酸化水平也降低。PIM2或eIF4E的过表达部分逆转了CHES1的抗增殖作用，表明PIM2和蛋白质生物合成是CHES1抗增殖作用的重要靶点。在几种人类造血癌症中，CHES1和PIM2的表达呈负相关，提示CHES1对PIM2的抑制在临床上具有相关性。
