ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer.

Fusion of the androgen receptor-regulated (AR-regulated) TMPRSS2 gene with ERG in prostate cancer (PCa) causes androgen-stimulated overexpression of ERG, an ETS transcription factor, but critical downstream effectors of ERG-mediating PCa development remain to be established. Expression of the SOX9 transcription factor correlated with TMPRSS2:ERG fusion in 3 independent PCa cohorts, and ERG-dependent expression of SOX9 was confirmed by RNAi in the fusion-positive VCaP cell line. SOX9 has been shown to mediate ductal morphogenesis in fetal prostate and maintain stem/progenitor cell pools in multiple adult tissues, and has also been linked to PCa and other cancers. SOX9 overexpression resulted in neoplasia in murine prostate and stimulated tumor invasion, similarly to ERG. Moreover, SOX9 depletion in VCaP cells markedly impaired invasion and growth in vitro and in vivo, establishing SOX9 as a critical downstream effector of ERG. Finally, we found that ERG regulated SOX9 indirectly by opening a cryptic AR-regulated enhancer in the SOX9 gene. Together, these results demonstrate that ERG redirects AR to a set of genes including SOX9 that are not normally androgen stimulated, and identify SOX9 as a critical downstream effector of ERG in TMPRSS2:ERG fusion-positive PCa.

[1]  M. Ittmann,et al.  Pleiotropic biological activities of alternatively spliced TMPRSS2/ERG fusion gene transcripts. , 2008, Cancer research.

[2]  M. Loda,et al.  Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  K. Pienta,et al.  A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. , 2007, Molecular cell.

[4]  M. Teitell,et al.  ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells , 2009, Proceedings of the National Academy of Sciences.

[5]  V. Vidal,et al.  SOX9 expression is a general marker of basal cell carcinoma and adnexal‐related neoplasms , 2008, Journal of cutaneous pathology.

[6]  N. Hanley,et al.  Understanding the role of SOX9 in acquired diseases: lessons from development. , 2011, Trends in molecular medicine.

[7]  T. Golub,et al.  Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. , 2006, Cancer research.

[8]  R. Kist,et al.  Sox9 is required for precursor cell expansion and extracellular matrix organization during mouse heart valve development. , 2007, Developmental biology.

[9]  M. Shen,et al.  Sox9 is required for prostate development. , 2008, Developmental biology.

[10]  Jennifer R. Rider,et al.  The TMPRSS2:ERG Rearrangement, ERG Expression, and Prostate Cancer Outcomes: A Cohort Study and Meta-analysis , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[11]  P. Nelson,et al.  A causal role for ERG in neoplastic transformation of prostate epithelium , 2008, Proceedings of the National Academy of Sciences.

[12]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[13]  D. Tindall,et al.  Androgen regulation of gene expression. , 2010, Advances in cancer research.

[14]  J. Tchinda,et al.  Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. , 2006, Science.

[15]  J. Deng,et al.  Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine , 2011, Nature Genetics.

[16]  R. Shah,et al.  Role of the TMPRSS2-ERG gene fusion in prostate cancer. , 2008, Neoplasia.

[17]  Manuel Serrano,et al.  Oncogenicity of the developmental transcription factor Sox9. , 2012, Cancer research.

[18]  L. Marchionni,et al.  An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer. , 2011, Cancer research.

[19]  C. Hsiung,et al.  Upregulation of SOX9 in Lung Adenocarcinoma and Its Involvement in the Regulation of Cell Growth and Tumorigenicity , 2010, Clinical Cancer Research.

[20]  Hongyun Wang,et al.  SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion. , 2008, Cancer research.

[21]  A. Malek,et al.  ETS Transcription Factors Control Transcription of EZH2 and Epigenetic Silencing of the Tumor Suppressor Gene Nkx3.1 in Prostate Cancer , 2010, PloS one.

[22]  J. Cuzick,et al.  SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation. , 2010, Cancer research.

[23]  Pier Paolo Pandolfi,et al.  Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate , 2009, Nature Genetics.

[24]  R. Teasdale,et al.  Twenty pairs of sox: extent, homology, and nomenclature of the mouse and human sox transcription factor gene families. , 2002, Developmental cell.

[25]  R. Kist,et al.  SOX9 is required for maintenance of the pancreatic progenitor cell pool , 2007, Proceedings of the National Academy of Sciences.

[26]  O. Kallioniemi,et al.  FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. , 2010, Cancer research.

[27]  L. Hennighausen,et al.  Conditional gene expression in secretory tissues and skin of transgenic mice using the MMTV‐LTR and the tetracycline responsive system , 1995, Journal of Cellular Biochemistry.

[28]  Sahar Mansour,et al.  Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene , 1994, Nature.

[29]  A. Chinnaiyan,et al.  Recurrent gene fusions in prostate cancer , 2008, Nature Reviews Cancer.

[30]  G Parmigiani,et al.  Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer , 2008, Oncogene.

[31]  Leif E. Peterson,et al.  Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. , 2007, Cancer cell.

[32]  L. Marchionni,et al.  Sox9 is required for prostate development and prostate cancer initiation , 2012, Oncotarget.

[33]  Clifford A. Meyer,et al.  Androgen Receptor Regulates a Distinct Transcription Program in Androgen-Independent Prostate Cancer , 2009, Cell.

[34]  C. Sander,et al.  Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis , 2009, Nature Genetics.

[35]  M. Lai,et al.  Analysis of SOX9 expression in colorectal cancer. , 2008, American journal of clinical pathology.

[36]  P. Nelson,et al.  Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. , 2011, Cancer cell.

[37]  J. Ortonne,et al.  Sox9 Is Essential for Outer Root Sheath Differentiation and the Formation of the Hair Stem Cell Compartment , 2005, Current Biology.

[38]  Wenjun Guo,et al.  Slug and Sox9 Cooperatively Determine the Mammary Stem Cell State , 2012, Cell.

[39]  S. Balk,et al.  Reactivation of androgen receptor-regulated TMPRSS2:ERG gene expression in castration-resistant prostate cancer. , 2009, Cancer research.

[40]  Tao Zhang,et al.  SOX9 is expressed in normal prostate basal cells and regulates androgen receptor expression in prostate cancer cells. , 2007, Cancer research.

[41]  Hans Clevers,et al.  SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes , 2004, The Journal of cell biology.

[42]  Carlos Cordon-Cardo,et al.  Pten is essential for embryonic development and tumour suppression , 1998, Nature Genetics.

[43]  M. Rubin,et al.  TMPRSS2-ERG Fusion Prostate Cancer: An Early Molecular Event Associated With Invasion , 2006, The American journal of surgical pathology.

[44]  S. Murakami,et al.  Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[45]  N. Tommerup,et al.  Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9 , 1994, Cell.

[46]  C. Hagel,et al.  Expression of SOX9 and SOX10 in Central Neuroepithelial Tumor , 2006, Journal of Neuro-Oncology.

[47]  Swneke D. Bailey,et al.  Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus , 2012, Genome research.

[48]  N. Palanisamy,et al.  Activation of NF-{kappa}B by TMPRSS2/ERG Fusion Isoforms through Toll-Like Receptor-4. , 2011, Cancer research.

[49]  M. Rubin,et al.  α‐Methylacyl‐CoA racemase expression and lethal prostate cancer in the Physicians' Health Study and Health Professionals Follow‐up Study , 2012, The Prostate.

[50]  Zhaohui S. Qin,et al.  An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. , 2010, Cancer cell.