title: ING4 regulates a secretory phenotype in primary fibroblasts with dual effects on cell proliferation and tumor growth.
abstract: ING proteins have an essential role in the control of a variety of cellular functions whose deregulation is associated with tumor formation and dissemination, such as proliferation, apoptosis, senescence or invasion. Accordingly, loss of function of ING proteins is a frequent event in many types of human tumors. In this report, we have studied the function of ING4, a member of the ING family of tumor suppressors, in the context of normal, non-transformed primary fibroblasts. We show that ING4 negatively regulates cell proliferation in this cell type. The antiproliferative action of ING4 requires its ability to recognize chromatin marks, it is p53-dependent at least in part, and it is lost in an ING4 cancer-associated mutant. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family. The secretory phenotype regulated by ING4 in primary fibroblasts displays a selective paracrine effect on proliferation, fostering the division of tumor cells, while inhibiting division in primary fibroblasts. Consistently, ING4-expressing fibroblasts promoted tumor growth in vivo in co-injection tumorigenesis assays. Collectively, our results show that ING4 not only can regulate the proliferation of primary non-transformed human fibroblasts, but also orchestrates a secretory phenotype in these cells that promotes tumor cell proliferation in vitro and in vivo. These findings support a critical role for ING4 expression in normal cells in the non-cell-autonomous regulation of tumor growth.
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Moreno
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Soleto
authors.affiliation: 1] Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, Madrid, Spain [2] Departamento de Bioquímica, Universidad Autónoma de Madrid, IdiPAZ (Instituto de Investigación Sanitaria La Paz) and Fundación MD Anderson Internacional, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: García-Sanz
authors.affiliation: 1] Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, Madrid, Spain [2] Departamento de Bioquímica, Universidad Autónoma de Madrid, IdiPAZ (Instituto de Investigación Sanitaria La Paz) and Fundación MD Anderson Internacional, Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Moreno-Bueno
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Palmero
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism*; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D025521:Tumor Suppressor Proteins