title: Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer.
abstract: Thalidomide is experimentally used to treat various human cancers; however, clinical responses to thalidomide are sporadic. Here we demonstrate that CUL4A plays an oncogenic role in prostate cancer development and prostate cancer cells with higher level of CUL4A are particularly sensitive to thalidomide treatment. We show that CUL4A is frequently overexpressed in human primary prostate cancer and cell lines. Notably, subjects with tumors that highly expressed CUL4A had poor overall survival. CUL4A downregulation inhibited cell proliferation and induced apoptosis in vitro and in vivo, whereas CUL4A overexpression transformed human normal prostate epithelial cells and promoted invasion, which was attenuated by the extracellular signal-regulated kinase (ERK) inhibitor. We further show that the sensitivity to thalidomide is positively correlated with CUL4A expression in a panel of prostate cell lines. Ectopic CUL4A expression greatly enhanced sensitivity to thalidomide, while its downregulation conferred resistance to this drug. Mechanistically, thalidomide decreased CUL4A in a time- and dose-dependent manner, consequently leading to inaction of ERK pathway. Finally, we show that cereblon level is correlated with CUL4A expression and downregulated in thalidomide-resistant prostate cancer cell. Our results offer the first evidence that CUL4A is a potential therapeutic target for prostate cancer and may serve as a biomarker for assessing prognosis of human prostate cancer and response to thalidomide treatment.
authors.affiliation: Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, No. 168, Changhai Rd, Yangpu District, Shanghai, 200433, China.
authors.forename: Shancheng
authors.initials: S
authors.lastname: Ren
authors.forename: Chuanliang
authors.initials: C
authors.lastname: Xu
authors.forename: Zilian
authors.initials: Z
authors.lastname: Cui
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Yu
authors.forename: Weidong
authors.initials: W
authors.lastname: Xu
authors.forename: Fubo
authors.initials: F
authors.lastname: Wang
authors.forename: Ji
authors.initials: J
authors.lastname: Lu
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Xu
authors.initials: X
authors.lastname: Gao
authors.forename: You
authors.initials: Y
authors.lastname: Liang
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Sun
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D034622:RNA Interference; D013792:Thalidomide / Q000494:pharmacology* / Q000627:therapeutic use; D046888:Tissue Array Analysis; D047368:Tumor Burden; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; C502543:CRBN protein, human; C114234:CUL4A protein, human; D044842:Cullin Proteins; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases