TY - JOUR
T1 - Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer
AU - Wang, Shan
AU - Kollipara, Rahul K.
AU - Srivastava, Nishi
AU - Li, Rui
AU - Ravindranathan, Preethi
AU - Hernandez, Elizabeth
AU - Freeman, Eva
AU - Humphries, Caroline G.
AU - Kapur, Payal
AU - Lotan, Yair
AU - Fazli, Ladan
AU - Gleave, Martin E.
AU - Plymate, Stephen R.
AU - Raj, Ganesh
AU - Hsieh, Jer-Tsong
AU - Kittler, Ralf
PY - 2014/3/18
Y1 - 2014/3/18
N2 - The transcription factor E-twenty-six related gene (ERG), which is overexpressed through gene fusion with the androgen-responsive gene transmembrane protease, serine 2 (TMPRSS2) in ̃40% of prostate tumors, is a key driver of prostate carcinogenesis. Ablation of ERG would disrupt a key oncogenic transcriptional circuit and could be a promising therapeutic strategy for prostate cancer treatment. Here, we show that ubiquitin-specific peptidase 9, X-linked (USP9X), a deubiquitinase enzyme, binds ERG in VCaP prostate cancer cells expressing TMPRSS2-ERG and deubiquitinates ERG in vitro. USP9X knockdown resulted in increased levels of ubiquitinated ERG and was coupled with depletion of ERG. Treatment with the USP9X inhibitor WP1130 resulted in ERG degradation both in vivo and in vitro, impaired the expression of genes enriched in ERG and prostate cancer relevant gene signatures in microarray analyses, and inhibited growth of ERG-positive tumors in three mouse xenograft models. Thus, we identified USP9X as a potential therapeutic target in prostate cancer cells and established WP1130 as a lead compound for the development of ERGdepleting drugs.
AB - The transcription factor E-twenty-six related gene (ERG), which is overexpressed through gene fusion with the androgen-responsive gene transmembrane protease, serine 2 (TMPRSS2) in ̃40% of prostate tumors, is a key driver of prostate carcinogenesis. Ablation of ERG would disrupt a key oncogenic transcriptional circuit and could be a promising therapeutic strategy for prostate cancer treatment. Here, we show that ubiquitin-specific peptidase 9, X-linked (USP9X), a deubiquitinase enzyme, binds ERG in VCaP prostate cancer cells expressing TMPRSS2-ERG and deubiquitinates ERG in vitro. USP9X knockdown resulted in increased levels of ubiquitinated ERG and was coupled with depletion of ERG. Treatment with the USP9X inhibitor WP1130 resulted in ERG degradation both in vivo and in vitro, impaired the expression of genes enriched in ERG and prostate cancer relevant gene signatures in microarray analyses, and inhibited growth of ERG-positive tumors in three mouse xenograft models. Thus, we identified USP9X as a potential therapeutic target in prostate cancer cells and established WP1130 as a lead compound for the development of ERGdepleting drugs.
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U2 - 10.1073/pnas.1322198111
DO - 10.1073/pnas.1322198111
M3 - Article
C2 - 24591637
AN - SCOPUS:84896502088
SN - 0027-8424
VL - 111
SP - 4251
EP - 4256
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -