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

Oncogene volume 36, pages 2172–2183 (2017)Cite this article

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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.

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Acknowledgements

We thank Drs Berton Zbar, Steve Bova and Tammy Naab for comments; and Lisa Garland, Mary Thompson and Allen Kane for technical assistance. This work is supported in part by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and by Leidos Biomedical Research, Inc., under contract # HHSN261200800001E. The content 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 US government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no conflicts to disclose. Financial Support: This work is supported in part by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute and by Leidos Biomedical Research, Inc., under contract # HHSN261200800001E.

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  1. M L Nickerson & M Dean

    Present address: 14Current address: Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA.,

Authors and Affiliations

  1. Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA

    M L Nickerson, S Turan, H Li, H Lou, K Misner, W Tan, S K Anderson & M Dean

  2. Protein Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    S Das & T Andresson

  3. Data Science for Genomics, Ellicott City, MD, USA

    K M Im

  4. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    S I Berndt, S A Brodie, A J Bouk, Z Wang, W Y Huang, R N Hoover, M A Tucker, J Boland, L E Moore, S J Chanock & M Yeager

  5. Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    H Li, H Lou & W Tan

  6. Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    S A Brodie, A J Bouk, J Boland & M Yeager

  7. Ingenuity Systems, Inc., Redwood City, CA, USA

    J N Billaud

  8. Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA

    T Zhang & K Brown

  9. Pathology and Histotechnology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    D Butcher

  10. Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA

    L Sun & J R Keller

  11. Department of Pathology, Howard University College of Medicine, Howard University Hospital, NW, Washington, DC, USA

    A Esnakula

  12. Protein Expression Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    D Esposito

  13. School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    W B Isaacs

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  1. M L Nickerson
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Correspondence to M L Nickerson.

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Nickerson, M., Das, S., Im, K. et al. TET2 binds the androgen receptor and loss is associated with prostate cancer. Oncogene 36, 2172–2183 (2017). https://doi.org/10.1038/onc.2016.376

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