title: ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer.
abstract: 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.
authors: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Changmeng
authors: C
authors: Cai
authors: Hongyun
authors: H
authors: Wang
authors: Housheng Hansen
authors: HH
authors: He
authors: Sen
authors: S
authors: Chen
authors: Lingfeng
authors: L
authors: He
authors: Fen
authors: F
authors: Ma
authors: Lorelei
authors: L
authors: Mucci
authors: Qianben
authors: Q
authors: Wang
authors: Christopher
authors: C
authors: Fiore
authors: Adam G
authors: AG
authors: Sowalsky
authors: Massimo
authors: M
authors: Loda
authors: X Shirley
authors: XS
authors: Liu
authors: Myles
authors: M
authors: Brown
authors: Steven P
authors: SP
authors: Balk
authors: Xin
authors: X
authors: Yuan
mesh_terms: D000728:Androgens / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D013196:Dihydrotestosterone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D000071230:Transcriptional Regulator ERG; D059467:Transcriptome
chemical_list: D000728:Androgens; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D011944:Receptors, Androgen; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D013196:Dihydrotestosterone