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ING4 regulates a secretory phenotype in primary fibroblasts with dual effects on cell proliferation and tumor growth

ABSTRACT: ING proteins play 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 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. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family.

ORGANISM(S): Homo sapiens

PROVIDER: GSE42412 | GEO | 2013/04/22

SECONDARY ACCESSION(S): PRJNA181347

REPOSITORIES: GEO

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ING4 regulates a secretory phenotype in primary fibroblasts with dual effects on cell proliferation and tumor growth

Project description:ING proteins play 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 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. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family. Two independent retroviral infections were performed in early pasaje IMR-90 fibroblasts with wild-type ING4 wild type and the N214D mutant. All of them were hibridazed by duplicate againts a reference sample from vector-infected cells

2013-04-22 | E-GEOD-42412 | biostudies-arrayexpress

Homo sapiens

Project description:ING4 regulates a secretory phenotype in primary fibroblasts with dual effects on cell proliferation and tumor growth

| PRJNA181347 | ENA

ING4 ChIP-chip in HT1080 cells

Project description:Aberrations in chromatin dynamics play a fundamental role in tumorigenesis, yet relatively little is known of the molecular mechanisms linking histone lysine methylation to neoplastic disease. ING4 (Inhibitor of Growth 4) is a native subunit of an HBO1 histone acetyltransferase (HAT) complex and a tumor suppressor protein. Here we show a critical role for the specific read-out of histone H3 trimethylated at lysine 4 (H3K4me3) by the ING4 PHD finger in mediating ING4 gene expression and tumor suppressor functions. The interaction between ING4 and H3K4me3 augments the acetylation activity of HBO1 on H3 tails, and drives H3 acetylation at ING4 target promoters to effect a DNA damage-dependent gene expression program. Further, ING4 facilitates apoptosis in response to genotoxic stress and inhibits anchorage-independent cell growth, and these functions are dependent on ING4 interactions with H3K4me3. Together, our results demonstrate a mechanism for brokering crosstalk between H3K4 methylation and histone H3 acetylation, and reveal a new molecular link between chromatin modulation and tumor suppressor mechanisms. ING4 ChIP-chip +/- Doxorubicin treatment in HT1080 cells on Nimblegen whole genome promoter array 4 samples: HT1080 cell lines stably expressing Flag-ING4 or Flag-ING4-D213A, +/- doxorubicin

2010-05-17 | E-GEOD-13412 | biostudies-arrayexpress

Analysis of gene expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus

Project description:The ING familiy of tumor suppressor proteins control several cellular functions relevant to anti-tumor protection, like cell-cycle control, apoptosis, senescence or migration. ING proteins are functionally linked to the p53 pathway, and they participate in transcriptional control via the recognition of histone marks and recruitment of protein complexes with chromatin-modifying activity to specific promoters. Here, we have investigated the global impact of ING1 in gene regulation through genome-wide analysis of expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus. We find that Ing1 has a predominant role as transcriptional repressor in this setting, affecting the expression of genes involved in a variety of cellular functions. Within the subset of genes showing differential expression, we have identified DGCR8, a protein involved in the early steps of microRNA biogenesis. In this study we have taken an unbiased approach to identify Ing1 targets, consisting in the comparison of expression profiles by genome-wide microarray analysis (Codelink mouse whole-genome expression microarrays), of mouse embryonic fibroblasts from embryos with the Ing1 locus inactivated by the insertion of a gene trap cassette, and their wild-type littermates. Three biological replicates were done for each phenotype.

2010-10-01 | E-GEOD-18519 | biostudies-arrayexpress

Regulation of the microRNA processor DGCR8 by the tumor suppressor ING1

Project description:The ING familiy of tumor suppressor proteins control several cellular functions relevant to anti-tumor protection, like cell-cycle control, apoptosis, senescence or migration. ING proteins are functionally linked to the p53 pathway, and they participate in transcriptional control via the recognisition of histone marks and recruitment of protein complexes with chromatin-modifying activity to specific promoters. Here, we have investigated the global impact of ING1 in gene regulation through genome-wide analysis of expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus. We find that Ing1 has a predominant role as transcriptional repressor in this setting, affecting the expression of genes involved in a variety of cellular functions. Within the subset of genes showing differential expression, we have identified DGCR8, a protein involved in the early steps of microRNA biogenesis. We show that ING1 binds to the DGCR8 promoter and controls its transcription through chromatin regulation at its promoter. We also find that ING1 and DGCR8 can cooperate in restraining proliferation. In summary, this study reveals a novel connection between ING1 and a regulator of microRNA biogenesis, and identifies new links between tumor suppressor proteins and the microRNA machinery For MEFs, two replicates were used for each genotype (wild-type or Ing1-deficient). Wild type MEFs were used as reference. For EMG cells [a cell line generated in our laboratory], two replicates were used for each condition (cells where ING1 was induced by doxycycline or uninduced cells). Uninduced cells were used as reference.

2010-06-20 | E-GEOD-18645 | biostudies-arrayexpress

ING4 ChIP-chip in HT1080 cells

2008-11-05 | GSE13412 | GEO

Gene expression analysis of human cancer associated fibroblasts (CAFs) stimulated with Platelet-Derived Growth Factor (PDGF)-CC

Project description:This study is part of a larger effort set to determine the factors requried for the crosstalk between tumor cells and fibroblasts in breast cancer. Specifically, the primary aim of this microarray analysis is to detail the soluble factors secreted by cancer-asociated fibroblasts following stmulation with PDGF-CC.

2018-03-06 | GSE108835 | GEO

Regulation of the microRNA processor DGCR8 by the tumor suppressor ING1

Project description:The ING familiy of tumor suppressor proteins control several cellular functions relevant to anti-tumor protection, like cell-cycle control, apoptosis, senescence or migration. ING proteins are functionally linked to the p53 pathway, and they participate in transcriptional control via the recognisition of histone marks and recruitment of protein complexes with chromatin-modifying activity to specific promoters. Here, we have investigated the global impact of ING1 in gene regulation through genome-wide analysis of expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus. We find that Ing1 has a predominant role as transcriptional repressor in this setting, affecting the expression of genes involved in a variety of cellular functions. Within the subset of genes showing differential expression, we have identified DGCR8, a protein involved in the early steps of microRNA biogenesis. We show that ING1 binds to the DGCR8 promoter and controls its transcription through chromatin regulation at its promoter. We also find that ING1 and DGCR8 can cooperate in restraining proliferation. In summary, this study reveals a novel connection between ING1 and a regulator of microRNA biogenesis, and identifies new links between tumor suppressor proteins and the microRNA machinery

2009-10-21 | GSE18645 | GEO

Analysis of gene expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus

2010-10-01 | GSE18519 | GEO

GDE3 regulates oligodendrocyte precursor proliferation via release of soluble CNTFRα

Project description:GDE3 regulates oligodendrocyte precursor proliferation via release of soluble CNTFRα

| PRJNA560200 | ENA