title: 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: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
authors: Min-Zu
authors: MZ
authors: Wu
authors: Department of Dental Hygiene, China Medical University, Taichung, Taiwan. Department of Pathology, National Defense Medical Centre and Tri-Service General Hospital, Taipei, Taiwan.
authors: Su-Feng
authors: SF
authors: Chen
authors: Department of Pathology, National Defense Medical Centre and Tri-Service General Hospital, Taipei, Taiwan.
authors: Shin
authors: S
authors: Nieh
authors: Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California.
authors: Christopher
authors: C
authors: Benner
authors: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors: Luo-Ping
authors: LP
authors: Ger
authors: Department of Pathology, China Medical University and Hospital, Taichung, Taiwan.
authors: Chia-Ing
authors: CI
authors: Jan
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
authors: Li
authors: L
authors: Ma
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
authors: Chien-Hung
authors: CH
authors: Chen
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
authors: Tomoaki
authors: T
authors: Hishida
authors: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors: Hong-Tai
authors: HT
authors: Chang
authors: Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Centre and Tri-Service General Hospital, Taipei, Taiwan. Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors: Yaoh-Shiang
authors: YS
authors: Lin
authors: Department of Medical Oncology, Hospital Clinic Barcelona, Barcelona University, Barcelona, Spain.
authors: Nuria
authors: N
authors: Montserrat
authors: Department of Medical Oncology, Hospital Clinic Barcelona, Barcelona University, Barcelona, Spain.
authors: Pedro
authors: P
authors: Gascon
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California.
authors: Ignacio
authors: I
authors: Sancho-Martinez
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California. belmonte@salk.edu.
authors: Juan Carlos
authors: JC
authors: Izpisua Belmonte
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003596:Cytosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D049308:Dioxygenases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D006899:Mixed Function Oxygenases; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000201:enzymology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C578792:TET3 protein, human; D049308:Dioxygenases; D048051:p38 Mitogen-Activated Protein Kinases