Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer

Prostate cancer (PCa) is a major lethal malignancy in men, but the molecular events and their interplay underlying prostate carcinogenesis remain poorly understood. Epigenetic events and the upregulation of polycomb group silencing proteins including Bmi1 have been described to occur during PCa prog...

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Bibliographic Details
Published in:The Journal of clinical investigation Vol. 122; no. 5; pp. 1920 - 1932
Main Authors: Nacerddine, Karim, Beaudry, Jean-Bernard, Ginjala, Vasudeva, Westerman, Bart, Mattiroli, Francesca, Song, Ji-Ying, Van Der Poel, Henk, Ponz, Olga Balague, Pritchard, Colin, Cornelissen-Steijger, Paulien, Zevenhoven, John, Tanger, Ellen, Sixma, Titia K, Ganesan, Shridar, Van Lohuizen, Maarten
Format: Journal Article
Language:English
Published: American Society for Clinical Investigation 01.05.2012
Subjects:
Development and progression
DNA damage
Genetic aspects
Ligases
Oncogenes
Phosphorylation
Prostate cancer
ISSN:0021-9738
Online Access:Get full text
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Summary:Prostate cancer (PCa) is a major lethal malignancy in men, but the molecular events and their interplay underlying prostate carcinogenesis remain poorly understood. Epigenetic events and the upregulation of polycomb group silencing proteins including Bmi1 have been described to occur during PCa progression. Here, we found that conditional overexpression of Bmi1 in mice induced prostatic intraepithelial neoplasia, and elicited invasive adenocarcinoma when combined with PTEN haploinsufficiency. In addition, Bmi1 and the PI3K/Akt pathway were coactivated in a substantial fraction of human high-grade tumors. We found that Akt mediated Bmi1 phosphorylation, enhancing its oncogenic potential in an Ink4a/Arf-independent manner. This process also modulated the DNA damage response and affected genomic stability. Together, our findings demonstrate the etiological role of Bmi1 in PCa, unravel an oncogenic collaboration between Bmi1 and the PI3K/Akt pathway, and provide mechanistic insights into the modulation of Bmi1 function by phosphorylation during prostate carcinogenesis.
ISSN:0021-9738
DOI:10.1172/JCI57477.