title: CHES1/FOXN3 regulates cell proliferation by repressing PIM2 and protein biosynthesis.
abstract: 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.
authors.affiliation: Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Huot
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vernier
authors.forename: Véronique
authors.initials: V
authors.lastname: Bourdeau
authors.forename: Laurent
authors.initials: L
authors.lastname: Doucet
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Saint-Germain
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Gaumont-Leclerc
authors.forename: Alejandro
authors.initials: A
authors.lastname: Moro
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D051858:Forkhead Transcription Factors; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D014176:Protein Biosynthesis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; C106158:FOXN3 protein, human; D051858:Forkhead Transcription Factors; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D017346:Protein Serine-Threonine Kinases