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Series GSE60434 Query DataSets for GSE60434
Status Public on Oct 05, 2015
Title Hypoxia-induced TET-TNFa-p38-MAPK signaling axis drives tumor malignancy of human breast cancer
Organism Homo sapiens
Experiment type Methylation profiling by high throughput sequencing
Summary Hypoxia, a hallmark of most solid tumors, leads to aberrations in epigenetic modifications promoting malignant tumor phenotypes, including metastatic features and stem cell-like characteristics. Aberrant DNA methylation has been considered to play an essential role during tumor progression and tightly associate with tumor malignancy. However, the mechanism by which hypoxia alters DNA methylation to promote tumor malignancy remains poorly understood. Ten-eleven translocation 1-3 (TET1-3) proteins, which catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), play a critical role in the DNA demethylation that controls different biological processes. Here we demonstrate that the expression of TET1 and TET3 is closely associated with tumor hypoxia, tumor malignancy and poor prognosis of patients with breast cancer. Hypoxia results in deregulation of TET1 and TET3, leading to breast tumor initiating cell (BTIC) properties. Mechanically, hypoxia regulates expression of TET1 and TET3 via hypoxia-inducible factor-1a (HIF-1a), thereby resulting in 5hmC genome-wide changes, which in turn leads to the upregulation of TNFa expression and activation of its downstream p38-MAPK pathway. Importantly, signal transduction through the TET-TNFa-p38-MAPK signaling axis is required for the acquisition of BTIC characteristics and chemotherapy resistance, leading to more malignant tumor phenotypes. Inhibition of the hypoxia-TET-TNF╬▒-p38-MAPK signaling pathway results in compromised BTIC properties and tumorigenicity in vitro and in vivo, suggesting a possible therapeutic strategy.
 
Overall design Examination of 5hmc profile in MCF7 breast cancer cell line with or without hypoxia treatment using hMeDIP-Seq
 
Contributor(s) Wu M, Benner C, Carlos J, Belmonte I
Citation(s) 26294212
Submission date Aug 14, 2014
Last update date May 15, 2019
Contact name Christopher Benner
E-mail(s) cbenner@ucsd.edu
Organization name University of California, San Diego (UCSD)
Department Medicine
Street address 9500 Gilman Dr. MC 0640
City La Jolla
State/province California
ZIP/Postal code 92093-0640
Country USA
 
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (2)
GSM1479831 5hmc-MeDIP-MCF7-hypoxia
GSM1479832 5hmc-MeDIP-MCF7-normoxia
Relations
BioProject PRJNA258230
SRA SRP045510

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE60434_RAW.tar 399.6 Mb (http)(custom) TAR (of BIGWIG)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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