Abstract
Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylated cytosine (5-hmC) is an epigenetic mark potentially important in cancer. Here we report that 5-hmC is an epigenetic hallmark of prostate cancer (PCa) progression. A member of the ten-eleven translocation (TET) proteins, which catalyse the oxidation of methylated cytosine (5-mC) to 5-hmC, TET2, is repressed by androgens in PCa. Androgen receptor (AR)-mediated induction of the miR-29 family, which targets TET2, are markedly enhanced in hormone refractory PCa (HRPC) and its high expression predicts poor outcome of PCa patients. Furthermore, decreased expression of miR-29b results in reduced tumour growth and increased TET2 expression in an animal model of HRPC. Interestingly, global 5-hmC modification regulated by miR-29b represses FOXA1 activity. A reduction in 5-hmC activates PCa-related key pathways such as mTOR and AR. Thus, DNA modification directly links the TET2-dependent epigenetic pathway regulated by AR to 5-hmC-mediated tumour progression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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5-Methylcytosine / analogs & derivatives
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Aged
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Androgens / metabolism*
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Animals
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation
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Chromatin Immunoprecipitation
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Cytosine / analogs & derivatives*
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Cytosine / metabolism
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DNA Methylation
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Dioxygenases
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Disease Progression
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Epigenesis, Genetic
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Gene Expression Regulation, Neoplastic*
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HEK293 Cells
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Hepatocyte Nuclear Factor 3-alpha / genetics
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Humans
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Hydroxylation
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Immunohistochemistry
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Male
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Mice, Inbred BALB C
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MicroRNAs / genetics*
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Middle Aged
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Neoplasm Transplantation
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RNA, Messenger / metabolism*
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Receptors, Androgen / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Analysis, RNA
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TOR Serine-Threonine Kinases / metabolism
Substances
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Androgens
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DNA-Binding Proteins
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FOXA1 protein, human
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Hepatocyte Nuclear Factor 3-alpha
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MIRN29a microRNA, human
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MicroRNAs
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Androgen
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5-hydroxymethylcytosine
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5-Methylcytosine
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Cytosine
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Dioxygenases
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TET2 protein, human
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TOR Serine-Threonine Kinases
Associated data
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GEO/GSE58309
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GEO/GSE58428
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GEO/GSE62492
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GEO/GSE66039