Publication Date:
2012-12-04
Description:
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)-beta signalling triggered by PTEN loss will form a growth barrier as a defence mechanism to constrain prostate cancer progression, underscoring that TGF-beta 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-beta-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-beta signalling. These findings reveal that the destruction of the TGF-beta-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022346/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022346/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qin, Jun -- Wu, San-Pin -- Creighton, Chad J -- Dai, Fangyan -- Xie, Xin -- Cheng, Chiang-Min -- Frolov, Anna -- Ayala, Gustavo -- Lin, Xia -- Feng, Xin-Hua -- Ittmann, Michael M -- Tsai, Shaw-Jenq -- Tsai, Ming-Jer -- Tsai, Sophia Y -- DK45641/DK/NIDDK NIH HHS/ -- DK59820/DK/NIDDK NIH HHS/ -- DK62434/DK/NIDDK NIH HHS/ -- HL76448/HL/NHLBI NIH HHS/ -- P01 DK059820/DK/NIDDK NIH HHS/ -- P30 CA125123/CA/NCI NIH HHS/ -- P30 DK079638/DK/NIDDK NIH HHS/ -- P30DK079638/DK/NIDDK NIH HHS/ -- R01 DK045641/DK/NIDDK NIH HHS/ -- R01 HL076448/HL/NHLBI NIH HHS/ -- U19 DK062434/DK/NIDDK NIH HHS/ -- England -- Nature. 2013 Jan 10;493(7431):236-40. doi: 10.1038/nature11674. Epub 2012 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201680" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
COUP Transcription Factor II/deficiency/genetics/*metabolism
;
Cell Cycle Checkpoints
;
Cell Line, Tumor
;
*Cell Transformation, Neoplastic
;
Disease Models, Animal
;
Disease Progression
;
Gene Deletion
;
Humans
;
Male
;
Mice
;
Neoplasm Metastasis
;
PTEN Phosphohydrolase/deficiency/genetics
;
Proportional Hazards Models
;
Prostate/metabolism/pathology
;
Prostatic Neoplasms/*metabolism/*pathology
;
*Signal Transduction
;
Smad4 Protein/deficiency/genetics/metabolism
;
Transforming Growth Factor beta/*antagonists & inhibitors/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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