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Cell cycle-coupled expansion of AR activity promotes cancer progression

Oncogene volume 36, pages 1655–1668 (2017)Cite this article

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Abstract

The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle ('Cell Cycle Common'), versus those that were specifically enriched in a subset of cell cycle phases ('Phase Restricted'). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide desaturase 1 was identified as an AR-regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.

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Acknowledgements

We gratefully thank Mandeep Takhar for her assistance in providing microarray data analysis, K Knudsen lab members for their input, Bin Fang for assistance in creation of motif diagrams and E Schade for graphical support and expertise. This work was supported by grants to WL (R01HG007538 and R01CA193466), SGZ by the PCF, and to KEK by grants from the NCI (CA159945, CA176401), P30-CA056036, and in part by a grant to KEK with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions.

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Authors and Affiliations

  1. Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    C McNair, C E S Comstock, M A Augello, J F Goodwin, M J Schiewer, A Ertel & K E Knudsen

  2. Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospitals, Oslo, Norway

    A Urbanucci & I G Mills

  3. Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospitals, Oslo, Norway

    A Urbanucci & I G Mills

  4. Cambridge Research Institute, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    R Launchbury & J S Carroll

  5. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    S G Zhao

  6. Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, , Rochester, MN, USA

    J Karnes & L Wang

  7. GenomeDx Biosciences, , San Diego, CA, USA

    E Davicioni

  8. Ohio State University College of Medicine, , Columbus, OH, USA

    Q Wang

  9. Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK

    I G Mills

  10. Department of Radiation Oncology, Urology, and Medicine and Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, , San Francisco, CA, USA

    F Y Feng

  11. Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    W Li

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McNair, C., Urbanucci, A., Comstock, C. et al. Cell cycle-coupled expansion of AR activity promotes cancer progression. Oncogene 36, 1655–1668 (2017). https://doi.org/10.1038/onc.2016.334

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