Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells.
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ABSTRACT:
SUBMITTER: Chen R
PROVIDER: S-EPMC5744998 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The microenvironment of solid tumors is characterized by oxygen and glucose deprivation. Acss2/HIF-2 signaling coordinates essential genetic regulators including acetate-dependent acetyl CoA synthetase 2 (Acss2), Creb binding protein (Cbp), Sirtuin 1 (Sirt1), and Hypoxia Inducible Factor 2α (HIF-2α). We previously shown in mice that exogenous acetate augments growth and metastasis of flank tumors derived from fibrosarcoma-derived HT1080 cells in an Acss2/HIF-2 dependent manner. Colonic epithelial cells are exposed to the highest acetate levels in the body. We reasoned that colon cancer cells, like fibrosarcoma cells, may respond to acetate in a pro-growth manner. In this study, we examine the role of Acss2/HIF-2 signaling in colon cancer. We find that Acss2/HIF-2 signaling is activated by oxygen or glucose deprivation in two human colon cancer-derived cell lines, HCT116 and HT29, and is crucial for colony formation, migration, and invasion in cell culture studies. Flank tumors derived from HCT116 and HT29 cells exhibit augmented growth in mice when supplemented with exogenous acetate in an Acss2/HIF-2 dependent manner. Finally, Acss2 in human colon cancer samples is most frequently localized in the nucleus, consistent with it having a signaling role. Targeted inhibition of Acss2/HIF-2 signaling may have synergistic effects for some colon cancer patients.
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Project description:Subpopulations of primary Human Mammary Epithelial Cells (HMEC) have the unique ability to escape a period of growth arrest and continue to proliferate. These cells, called post-selection or variant cells (vHMEC), share features with premalignant breast cancer lesions, including p16INK4A promoter hypermethylation. Epigenetic silencing of tumour suppressor genes through DNA methylation and histone modification is an early event in tumorigenesis. One of the main challenges is to find genes or gene pathways that are commonly silenced to provide early epigenetic diagnostic and therapeutic cancer targets. To identify very early epigenetic events that occur in breast cancer, we used microarrays to screen for gene pathways that were suppressed in post-selection HMECs, but reactivated after treatment with the demethylation agent 5-Aza-2’-deoxycytidine (5-Aza-dC). We found several members of the Transforming Growth Factor Beta (TGFb) signalling pathway (THBS1, TGFb2, TGFb R1 & TGFb R2) were consistently down-regulated in the post-selection HMEC population. Gene suppression was not associated with DNA methylation but was associated with chromatin remodelling, involving a decrease in histone H3 lysine 27 (H3K27) tri-methylation and an increase in histone H3 lysine 9 (H3K9) di-methylation and H3K9 de-acetylation. Similar epigenetic repression was also identified MDAMB453 breast cancer cells and in breast tumour samples. These results demonstrate for the first time that TGFb2, its receptors TGFb R1 & TGFb R2 and activator THBS1 are concordantly suppressed early in breast carcinogenesis by repressive histone modifications and indicate that the TGFb signalling pathway is a novel target for gene activation by epigenetic therapy. Keywords: cell differentiation, breast cancer, gene silencing, epigenetics Two-colour reference design was used. Two biological replicates were included in the study - Bre60 and Bre-80. Each cell line was sampled at pre-selection stage, post-selection stage and post AZA treatment. The post-selection stage was chosen as the reference sample, and a control post-post hybridisation included to assess variability across the assay.
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Project description:Hypoxia-inducible factor-1 (HIF-1) is a well-studied transcription factor mediating cellular adaptation to hypoxia. It also plays a crucial role under normoxic conditions, such as in inflammation, where its regulation is less well understood. The 3'-untranslated region (UTR) of HIF-1? mRNA is among the most conserved UTRs in the genome, hinting toward posttranscriptional regulation. To identify potential trans factors, we analyzed a large compilation of expression data. In contrast to its known function of being a negative regulator, we found that tristetraprolin (TTP) positively correlates with HIF-1 target genes. Mathematical modeling predicts that an additional level of posttranslational regulation of TTP can explain the observed positive correlation between TTP and HIF-1 signaling. Mechanistic studies revealed that TTP indeed changes its mode of regulation from destabilizing to stabilizing HIF-1? mRNA upon phosphorylation by p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2. Using a model of monocyte-to-macrophage differentiation, we show that TTP-driven HIF-1? mRNA stabilization is crucial for cell migration. This demonstrates the physiological importance of a hitherto-unknown mechanism for multilevel regulation of HIF-1? in normoxia.
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