Dataset Information

Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells.

ABSTRACT: Survival of cancer cells in the harsh tumor microenvironment, characterized by oxygen and glucose deprivation, requires rapid initiation of cytoprotective measures. Metabolites whose levels change during stress are ideal signaling cues, particularly if used in post-translational modifications of stress-responsive signal transducers. In cancer cells exposed to oxygen or glucose deprivation, there is an increase in cellular levels of acetate, a substrate for acetate-dependent acetyl CoA synthetase 2 (Acss2) that also stimulates translocation of Acss2 from the cytosol to the nucleus. Nuclear, but not cytosolic, Acss2 promotes acetylation of the stress-responsive Hypoxia Inducible Factor 2α (HIF-2α) subunit by the acetyltransferase/coactivator Creb binding protein (Cbp), a process that facilitates stable Cbp/HIF-2α complex formation. In addition to promoting de novo transcription, Cbp and HIF-2α act in concert to regulate local histone 3 epigenetic marks. Exogenous acetate augments Acss2/HIF-2 dependent cancer growth and metastasis in cell culture and mouse models. Thus, an acetate switch in mammals links nutrient intake and stress signaling with tumor growth and metastasis.

SUBMITTER: Chen R

PROVIDER: S-EPMC5744998 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells.

Chen Rui R Xu Min M Nagati Jason J Garcia Joseph A JA

PloS one 20171227 12

Survival of cancer cells in the harsh tumor microenvironment, characterized by oxygen and glucose deprivation, requires rapid initiation of cytoprotective measures. Metabolites whose levels change during stress are ideal signaling cues, particularly if used in post-translational modifications of stress-responsive signal transducers. In cancer cells exposed to oxygen or glucose deprivation, there is an increase in cellular levels of acetate, a substrate for acetate-dependent acetyl CoA synthetase ...[more]

PMID: 29281714

Similar Datasets

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.

Dataset Information

Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells.

Publications

Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets