PMID- 27819678
OWN - NLM
STAT- MEDLINE
DCOM- 20170419
LR  - 20240216
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 36
IP  - 15
DP  - 2017 Apr
TI  - TET2 binds the androgen receptor and loss is associated with prostate cancer.
PG  - 2172-2183
LID - 10.1038/onc.2016.376 [doi]
AB  - Genetic alterations associated with prostate cancer (PCa) may be identified by 
      sequencing metastatic tumour genomes to identify molecular markers at this lethal 
      stage of disease. Previously, we characterized somatic alterations in metastatic 
      tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), 
      which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide 
      association studies previously identified non-coding risk variants associated 
      with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using 
      genotypes from the PEGASUS case-control cohort and identify six new risk variants 
      in introns 1 and 2. Oligonucleotides containing two risk variants are bound by 
      the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2 and 
      Oct1 expression are positively correlated in prostate tumours. TET2 is expressed 
      in normal prostate tissue and reduced in a subset of tumours from the Cancer 
      Genome Atlas (TCGA). Small interfering RNA-mediated TET2 knockdown (KD) increases 
      LNCaP cell proliferation, migration and wound healing, verifying loss drives a 
      cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and 
      AR-coactivator proteins in LNCaP cell extracts, and TET2 KD increases 
      prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 
      binding sites and hydroxymethylcytosine proximal to KLK3. A gene co-expression 
      network identified using TCGA prostate tumour RNA-sequencing identifies 
      co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate 
      metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated 
      BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression 
      signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 
      as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signalling. 
      Decreased TET2 mRNA expression in TCGA PCa tumours is strongly associated with 
      reduced patient survival, indicating reduced expression in tumours may be an 
      informative biomarker of disease progression and perhaps metastatic disease.
FAU - Nickerson, M L
AU  - Nickerson ML
AD  - Cancer and Inflammation Program, National Cancer Institute, National Institutes 
      of Health, Frederick, MD, USA.
FAU - Das, S
AU  - Das S
AD  - Protein Characterization Laboratory, Cancer Research Technology Program, Leidos 
      Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, 
      Frederick, MD, USA.
FAU - Im, K M
AU  - Im KM
AD  - Data Science for Genomics, Ellicott City, MD, USA.
FAU - Turan, S
AU  - Turan S
AD  - Cancer and Inflammation Program, National Cancer Institute, National Institutes 
      of Health, Frederick, MD, USA.
FAU - Berndt, S I
AU  - Berndt SI
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
FAU - Li, H
AU  - Li H
AUID- ORCID: 0000-0002-3501-4299
AD  - Cancer and Inflammation Program, National Cancer Institute, National Institutes 
      of Health, Frederick, MD, USA.
AD  - Basic Research Program, Leidos Biomedical Research, Inc., Frederick National 
      Laboratory for Cancer Research, Frederick, MD, USA.
FAU - Lou, H
AU  - Lou H
AD  - Cancer and Inflammation Program, National Cancer Institute, National Institutes 
      of Health, Frederick, MD, USA.
AD  - Basic Research Program, Leidos Biomedical Research, Inc., Frederick National 
      Laboratory for Cancer Research, Frederick, MD, USA.
FAU - Brodie, S A
AU  - Brodie SA
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
AD  - Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick 
      National Laboratory for Cancer Research, Frederick, MD, USA.
FAU - Billaud, J N
AU  - Billaud JN
AD  - Ingenuity Systems, Inc., Redwood City, CA, USA.
FAU - Zhang, T
AU  - Zhang T
AD  - Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, 
      USA.
FAU - Bouk, A J
AU  - Bouk AJ
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
AD  - Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick 
      National Laboratory for Cancer Research, Frederick, MD, USA.
FAU - Butcher, D
AU  - Butcher D
AD  - Pathology and Histotechnology Laboratory, Leidos Biomedical Research, Inc., 
      Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
FAU - Wang, Z
AU  - Wang Z
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
FAU - Sun, L
AU  - Sun L
AD  - Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of 
      Health, Frederick, MD, USA.
FAU - Misner, K
AU  - Misner K
AD  - Cancer and Inflammation Program, National Cancer Institute, National Institutes 
      of Health, Frederick, MD, USA.
FAU - Tan, W
AU  - Tan W
AD  - Cancer and Inflammation Program, National Cancer Institute, National Institutes 
      of Health, Frederick, MD, USA.
AD  - Basic Research Program, Leidos Biomedical Research, Inc., Frederick National 
      Laboratory for Cancer Research, Frederick, MD, USA.
FAU - Esnakula, A
AU  - Esnakula A
AD  - Department of Pathology, Howard University College of Medicine, Howard University 
      Hospital, NW, Washington, DC, USA.
FAU - Esposito, D
AU  - Esposito D
AD  - Protein Expression Laboratory, Leidos Biomedical Research, Inc., Frederick 
      National Laboratory for Cancer Research, Frederick, MD, USA.
FAU - Huang, W Y
AU  - Huang WY
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
FAU - Hoover, R N
AU  - Hoover RN
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
FAU - Tucker, M A
AU  - Tucker MA
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
FAU - Keller, J R
AU  - Keller JR
AD  - Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of 
      Health, Frederick, MD, USA.
FAU - Boland, J
AU  - Boland J
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
AD  - Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick 
      National Laboratory for Cancer Research, Frederick, MD, USA.
FAU - Brown, K
AU  - Brown K
AD  - Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, 
      USA.
FAU - Anderson, S K
AU  - Anderson SK
AD  - Cancer and Inflammation Program, National Cancer Institute, National Institutes 
      of Health, Frederick, MD, USA.
FAU - Moore, L E
AU  - Moore LE
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
FAU - Isaacs, W B
AU  - Isaacs WB
AD  - School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
FAU - Chanock, S J
AU  - Chanock SJ
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
FAU - Yeager, M
AU  - Yeager M
AD  - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, USA.
AD  - Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick 
      National Laboratory for Cancer Research, Frederick, MD, USA.
FAU - Dean, M
AU  - Dean M
AUID- ORCID: 0000-0003-2234-0631
AD  - Cancer and Inflammation Program, National Cancer Institute, National Institutes 
      of Health, Frederick, MD, USA.
FAU - Andresson, T
AU  - Andresson T
AD  - Protein Characterization Laboratory, Cancer Research Technology Program, Leidos 
      Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, 
      Frederick, MD, USA.
LA  - eng
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
GR  - Z99 CA999999/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
DEP - 20161107
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (AR protein, human)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Ketoglutaric Acids)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Androgen)
RN  - 0 (Succinates)
RN  - EC 1.13.11.- (Dioxygenases)
RN  - EC 1.13.11.- (TET2 protein, human)
RN  - EC 3.4.21.- (KLK3 protein, human)
RN  - EC 3.4.21.- (Kallikreins)
RN  - EC 3.4.21.77 (Prostate-Specific Antigen)
SB  - IM
MH  - Cell Proliferation/physiology
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Dioxygenases
MH  - HEK293 Cells
MH  - Humans
MH  - Introns
MH  - Kallikreins/genetics/metabolism
MH  - Ketoglutaric Acids/metabolism
MH  - Male
MH  - Polymorphism, Single Nucleotide
MH  - Prostate-Specific Antigen/genetics/metabolism
MH  - Prostatic Neoplasms/genetics/*metabolism/pathology
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Receptors, Androgen/genetics/*metabolism
MH  - Succinates/metabolism
PMC - PMC5391277
MID - NIHMS813752
COIS- Conflict of Interest: The authors declare no conflict of interest. The contents 
      of this publication does not necessarily reflect the views or policies of the 
      Department of Health and Human Services, nor does mention of trade names, 
      commercial products, or organizations imply endorsement by the U.S. government. 
      The funders had no role in study design, data collection and analysis, decision 
      to publish or preparation of the manuscript.
EDAT- 2016/11/08 06:00
MHDA- 2017/04/20 06:00
PMCR- 2017/05/07
CRDT- 2016/11/08 06:00
PHST- 2015/09/21 00:00 [received]
PHST- 2016/08/15 00:00 [revised]
PHST- 2016/08/29 00:00 [accepted]
PHST- 2016/11/08 06:00 [pubmed]
PHST- 2017/04/20 06:00 [medline]
PHST- 2016/11/08 06:00 [entrez]
PHST- 2017/05/07 00:00 [pmc-release]
AID - onc2016376 [pii]
AID - 10.1038/onc.2016.376 [doi]
PST - ppublish
SO  - Oncogene. 2017 Apr;36(15):2172-2183. doi: 10.1038/onc.2016.376. Epub 2016 Nov 7.