Cell cycle-coupled expansion of AR activity promotes cancer progression.
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.
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
C
C
McNair
Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospitals, Oslo, Norway.|Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospitals, Oslo, Norway.
A
A
Urbanucci
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
C E S
CE
Comstock
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
M A
MA
Augello
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
J F
JF
Goodwin
Cambridge Research Institute, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
R
R
Launchbury
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
S G
SG
Zhao
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
M J
MJ
Schiewer
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
A
A
Ertel
Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA.
J
J
Karnes
GenomeDx Biosciences, San Diego, CA, USA.
E
E
Davicioni
Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA.
L
L
Wang
Ohio State University College of Medicine, Columbus, OH, USA.
Q
Q
Wang
Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospitals, Oslo, Norway.|Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospitals, Oslo, Norway.|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
IG
Mills
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
FY
Feng
Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
W
0000-0001-9931-5990
W
Li
Cambridge Research Institute, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
J S
JS
Carroll
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
K E
KE
Knudsen
D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D059372:Nucleotide Motifs; D010641:Phenotype; D011379:Prognosis; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism*
D000728:Androgens; D011944:Receptors, Androgen
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