TET2 binds the androgen receptor and loss is associated with prostate cancer

M. L. Nickerson, S. Das, K. M. Im, S. Turan, S. I. Berndt, H. Li, H. Lou, S. A. Brodie, J. N. Billaud, T. Zhang, A. J. Bouk, D. Butcher, Z. Wang, L. Sun, K. Misner, W. Tan, A. Esnakula, D. Esposito, W. Y. Huang, R. N. Hoover & 11 others M. A. Tucker, J. R. Keller, J. Boland, K. Brown, S. K. Anderson, L. E. Moore, William B Isaacs, S. J. Chanock, M. Yeager, M. Dean, T. Andresson

Research output: Contribution to journalArticle

Abstract

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.Oncogene advance online publication, 7 November 2016; doi:10.1038/onc.2016.376.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Nov 7 2016

Fingerprint

Androgen Receptors
Prostatic Neoplasms
Neoplasms
Atlases
Genome
Prostate
Octamer Transcription Factors
RNA Sequence Analysis
Dioxygenases
Citric Acid Cycle
Neoplasm Genes
Genome-Wide Association Study
Succinic Acid
Prostate-Specific Antigen
Cell Extracts
Oncogenes
Oligonucleotides
Wound Healing
Introns
Small Interfering RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Nickerson, M. L., Das, S., Im, K. M., Turan, S., Berndt, S. I., Li, H., ... Andresson, T. (Accepted/In press). TET2 binds the androgen receptor and loss is associated with prostate cancer. Oncogene. https://doi.org/10.1038/onc.2016.376

TET2 binds the androgen receptor and loss is associated with prostate cancer. / Nickerson, M. L.; Das, S.; Im, K. M.; Turan, S.; Berndt, S. I.; Li, H.; Lou, H.; Brodie, S. A.; Billaud, J. N.; Zhang, T.; Bouk, A. J.; Butcher, D.; Wang, Z.; Sun, L.; Misner, K.; Tan, W.; Esnakula, A.; Esposito, D.; Huang, W. Y.; Hoover, R. N.; Tucker, M. A.; Keller, J. R.; Boland, J.; Brown, K.; Anderson, S. K.; Moore, L. E.; Isaacs, William B; Chanock, S. J.; Yeager, M.; Dean, M.; Andresson, T.

In: Oncogene, 07.11.2016.

Research output: Contribution to journalArticle

Nickerson, ML, Das, S, Im, KM, Turan, S, Berndt, SI, Li, H, Lou, H, Brodie, SA, Billaud, JN, Zhang, T, Bouk, AJ, Butcher, D, Wang, Z, Sun, L, Misner, K, Tan, W, Esnakula, A, Esposito, D, Huang, WY, Hoover, RN, Tucker, MA, Keller, JR, Boland, J, Brown, K, Anderson, SK, Moore, LE, Isaacs, WB, Chanock, SJ, Yeager, M, Dean, M & Andresson, T 2016, 'TET2 binds the androgen receptor and loss is associated with prostate cancer', Oncogene. https://doi.org/10.1038/onc.2016.376
Nickerson, M. L. ; Das, S. ; Im, K. M. ; Turan, S. ; Berndt, S. I. ; Li, H. ; Lou, H. ; Brodie, S. A. ; Billaud, J. N. ; Zhang, T. ; Bouk, A. J. ; Butcher, D. ; Wang, Z. ; Sun, L. ; Misner, K. ; Tan, W. ; Esnakula, A. ; Esposito, D. ; Huang, W. Y. ; Hoover, R. N. ; Tucker, M. A. ; Keller, J. R. ; Boland, J. ; Brown, K. ; Anderson, S. K. ; Moore, L. E. ; Isaacs, William B ; Chanock, S. J. ; Yeager, M. ; Dean, M. ; Andresson, T. / TET2 binds the androgen receptor and loss is associated with prostate cancer. In: Oncogene. 2016.
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AU - Nickerson, M. L.

AU - Das, S.

AU - Im, K. M.

AU - Turan, S.

AU - Berndt, S. I.

AU - Li, H.

AU - Lou, H.

AU - Brodie, S. A.

AU - Billaud, J. N.

AU - Zhang, T.

AU - Bouk, A. J.

AU - Butcher, D.

AU - Wang, Z.

AU - Sun, L.

AU - Misner, K.

AU - Tan, W.

AU - Esnakula, A.

AU - Esposito, D.

AU - Huang, W. Y.

AU - Hoover, R. N.

AU - Tucker, M. A.

AU - Keller, J. R.

AU - Boland, J.

AU - Brown, K.

AU - Anderson, S. K.

AU - Moore, L. E.

AU - Isaacs, William B

AU - Chanock, S. J.

AU - Yeager, M.

AU - Dean, M.

AU - Andresson, T.

PY - 2016/11/7

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N2 - 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.Oncogene advance online publication, 7 November 2016; doi:10.1038/onc.2016.376.

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