ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer
Changmeng Cai, Hongyun Wang, Housheng Hansen He, Sen Chen, Lingfeng He, Fen Ma, Lorelei Mucci, Qianben Wang, Christopher Fiore, Adam G. Sowalsky, Massimo Loda, X. Shirley Liu, Myles Brown, Steven P. Balk, Xin Yuan
Changmeng Cai, Hongyun Wang, Housheng Hansen He, Sen Chen, Lingfeng He, Fen Ma, Lorelei Mucci, Qianben Wang, Christopher Fiore, Adam G. Sowalsky, Massimo Loda, X. Shirley Liu, Myles Brown, Steven P. Balk, Xin Yuan
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Research Article Oncology

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

Changmeng Cai, Hongyun Wang, Housheng Hansen He, Sen Chen, Lingfeng He, Fen Ma, Lorelei Mucci, Qianben Wang, Christopher Fiore, Adam G. Sowalsky, Massimo Loda, X. Shirley Liu, Myles Brown, Steven P. Balk, Xin Yuan

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Figure 1

SOX9 expression is increased in TMPRSS2:ERG-positive PCa.

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SOX9 expression is increased in TMPRSS2:ERG-positive PCa. (A) Heat map...
(A) Heat maps (green, lower expression; red, higher expression) of Affymetrix microarray data showing mRNA expression for genes with increased levels in TMPRSS2:ERG fusion–positive versus TMPRSS2:ERG fusion–negative tumor subsets of both primary PCa and CRPC bone metastases (fold change of mean expression >1.5 and a 2-tailed Student’s t test P value < 0.05). (B) Quartile plot (mean and each quartile) of ERG and SOX9 expression. The differences between the fusion-positive and fusion-negative samples were *P < 0.05 or **P < 0.01 (2-tailed Student’s t test). (C) MSKCC dataset showing that SOX9 expression was significantly higher in ERG-positive tumors (based on the outlier expression of ERG, 47/103) versus ERG-negative tumors. Heat maps for ERG and SOX9 expression in individual tumors are shown in Supplemental Figure 1A. (D) SOX9 expression index based on SOX9 immunostaining intensity and fraction of positive cells (mean SOX9 addscore) are plotted for TMPRSS2:ERG fusion–positive versus –negative radical prostatectomy samples from the Physicians’ Health and Health Professionals Follow-up Studies.