title: Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer.
abstract: 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 ERG-depleting drugs.
authors.affiliation: Eugene McDermott Center for Human Growth and Development, Departments of Urology, Pathology, and Phamacology, Simmons Comprehensive Cancer Center, and Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.forename: Rahul K
authors.initials: RK
authors.lastname: Kollipara
authors.forename: Nishi
authors.initials: N
authors.lastname: Srivastava
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Preethi
authors.initials: P
authors.lastname: Ravindranathan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hernandez
authors.forename: Eva
authors.initials: E
authors.lastname: Freeman
authors.forename: Caroline G
authors.initials: CG
authors.lastname: Humphries
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
authors.forename: Ralf
authors.initials: R
authors.lastname: Kittler
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003487:Cyanoacrylates; D010450:Endopeptidases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D015513:Oncogene Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D003487:Cyanoacrylates; C531115:ERG protein, mouse; D009570:Nitriles; D015513:Oncogene Proteins; D011480:Protease Inhibitors; D011725:Pyridines; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; C519751:degrasyn; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; C404328:Usp9x protein, mouse