Hypoxia drives breast tumor malignancy through a TET-TNFα-p38-MAPK signaling axis

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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-hydroxymethyl-cytosine (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 tumor-igenicity in vitro and in vivo, with potential implications for how to eradicate BTIC as a therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)3912-3924
Number of pages13
JournalCancer Research
Volume75
Issue number18
DOIs
StatePublished - Sep 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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