title: COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis.
abstract: Mutations in phosphatase and tensin homologue (PTEN) or genomic alterations in the phosphatidylinositol-3-OH kinase-signalling pathway are the most common genetic alterations reported in human prostate cancer. However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire metastatic potential remains poorly understood. Recent studies suggest that upregulation of transforming growth factor (TGF)-β signalling triggered by PTEN loss will form a growth barrier as a defence mechanism to constrain prostate cancer progression, underscoring that TGF-β signalling might represent a pre-invasive checkpoint to prevent PTEN-mediated prostate tumorigenesis. Here we show that COUP transcription factor II (COUP-TFII, also known as NR2F2), a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-β-dependent checkpoint for PTEN-null indolent tumours. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumour. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biological significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumour recurrence and disease progression, whereas it is inversely associated with TGF-β signalling. These findings reveal that the destruction of the TGF-β-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease, and supports COUP-TFII as a potential drug target for the intervention of metastatic human prostate cancer.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: San-Pin
authors.initials: SP
authors.lastname: Wu
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Fangyan
authors.initials: F
authors.lastname: Dai
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.forename: Chiang-Min
authors.initials: CM
authors.lastname: Cheng
authors.forename: Anna
authors.initials: A
authors.lastname: Frolov
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ayala
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.forename: Shaw-Jenq
authors.initials: SJ
authors.lastname: Tsai
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tsai
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Tsai
mesh_terms: D000818:Animals; D051837:COUP Transcription Factor II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D016016:Proportional Hazards Models; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051837:COUP Transcription Factor II; D051059:PTEN Phosphohydrolase; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C497587:Nr2f2 protein, mouse; C490810:Smad4 protein, mouse; C494929:PTEN protein, human; C487757:Pten protein, mouse; C095569:NR2F2 protein, human