Hypoxia Drives Breast Tumor Malignancy through a TET-TNFα-p38-MAPK Signaling Axis.

Abstract

Hypoxia is a hallmark of solid tumors that drives malignant progression by altering epigenetic controls. In breast tumors, aberrant DNA methylation is a prevalent epigenetic feature associated with increased risk of metastasis and poor prognosis. However, the mechanism by which hypoxia alters DNA methylation or other epigenetic controls that promote breast malignancy remains poorly understood. We discovered that hypoxia deregulates TET1 and TET3, the enzymes that catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby leading to breast tumor-initiating cell (BTIC) properties. TET1/3 and 5hmC levels were closely associated with tumor hypoxia, tumor malignancy, and poor prognosis in breast cancer patients. Mechanistic investigations showed that hypoxia leads to genome-wide changes in DNA hydroxymethylation associated with upregulation of TNFα expression and activation of its downstream p38-MAPK effector pathway. Coordinate functions of TET1 and TET3 were also required to activate TNFα-p38-MAPK signaling as a response to hypoxia. Our results reveal how signal transduction through the TET-TNFα-p38-MAPK signaling axis is required for the acquisition of BTIC characteristics and tumorigenicity in vitro and in vivo, with potential implications for how to eradicate BTIC as a therapeutic strategy.

• Authors: Min-Zu Wu, Su-Feng Chen, Shin Nieh, Christopher Benner, Luo-Ping Ger, Chia-Ing Jan, Li Ma, Chien-Hung Chen, Tomoaki Hishida, Hong-Tai Chang, Yaoh-Shiang Lin, Nuria Montserrat, Pedro Gascon, Ignacio Sancho-Martinez, Juan Carlos Izpisua Belmonte
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 18 Pg. 3912-24 (Sep 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26294212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• DNA-Binding Proteins
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neoplasm Proteins
• Proto-Oncogene Proteins
• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha
• 5-hydroxymethylcytosine
• 5-Methylcytosine
• Cytosine
• Mixed Function Oxygenases
• TET1 protein, human
• TET3 protein, human
• Dioxygenases
• p38 Mitogen-Activated Protein Kinases

Topics

• 5-Methylcytosine (analogs & derivatives)
• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Hypoxia (genetics, physiology)
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Cytosine (analogs & derivatives, biosynthesis)
• DNA Methylation
• DNA-Binding Proteins (biosynthesis, genetics, physiology)
• Dioxygenases (biosynthesis, genetics, physiology)
• Female
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, genetics)
• Mice
• Mice, Nude
• Mixed Function Oxygenases
• Molecular Sequence Data
• Neoplasm Proteins (biosynthesis, genetics, physiology)
• Neoplastic Stem Cells (cytology, enzymology)
• Prognosis
• Promoter Regions, Genetic (genetics)
• Proto-Oncogene Proteins (biosynthesis, genetics, physiology)
• Recombinant Fusion Proteins (biosynthesis)
• Retrospective Studies
• Signal Transduction (physiology)
• Tumor Necrosis Factor-alpha (biosynthesis, genetics, physiology)
• p38 Mitogen-Activated Protein Kinases (physiology)