TET2 binds the androgen receptor and loss is associated with prostate cancer.
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.
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
M L
ML
Nickerson
Protein Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
S
S
Das
Data Science for Genomics, Ellicott City, MD, USA.
K M
KM
Im
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
S
S
Turan
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
S I
SI
Berndt
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.|Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
H
0000-0002-3501-4299
H
Li
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.|Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
H
H
Lou
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
S A
SA
Brodie
Ingenuity Systems, Inc., Redwood City, CA, USA.
J N
JN
Billaud
Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA.
T
T
Zhang
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
A J
AJ
Bouk
Pathology and Histotechnology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
D
D
Butcher
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Z
Z
Wang
Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
L
L
Sun
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
K
K
Misner
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.|Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
W
W
Tan
Department of Pathology, Howard University College of Medicine, Howard University Hospital, NW, Washington, DC, USA.
A
A
Esnakula
Protein Expression Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
D
D
Esposito
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
W Y
WY
Huang
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
R N
RN
Hoover
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
M A
MA
Tucker
Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
J R
JR
Keller
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
J
J
Boland
Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA.
K
K
Brown
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
S K
SK
Anderson
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
L E
LE
Moore
School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
W B
WB
Isaacs
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
S J
SJ
Chanock
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
M
M
Yeager
Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
M
0000-0003-2234-0631
M
Dean
Protein Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
T
T
Andresson
D049109:Cell Proliferation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D057809:HEK293 Cells; D006801:Humans; D007438:Introns; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013386:Succinates / Q000378:metabolism
C410798:AR protein, human; D004268:DNA-Binding Proteins; D007656:Ketoglutaric Acids; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D013386:Succinates; D049308:Dioxygenases; C541081:TET2 protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen