Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer
Karim Nacerddine, … , Shridar Ganesan, Maarten van Lohuizen
Karim Nacerddine, … , Shridar Ganesan, Maarten van Lohuizen
Published April 16, 2012
Citation Information: J Clin Invest. 2012;122(5):1920-1932. https://doi.org/10.1172/JCI57477.
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Research Article Oncology

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

Abstract

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.

Authors

Karim Nacerddine, Jean-Bernard Beaudry, Vasudeva Ginjala, Bart Westerman, Francesca Mattiroli, Ji-Ying Song, Henk van der Poel, Olga Balagué Ponz, Colin Pritchard, Paulien Cornelissen-Steijger, John Zevenhoven, Ellen Tanger, Titia K. Sixma, Shridar Ganesan, Maarten van Lohuizen

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Figure 3

Bmi1 expression and activation of PI3K/Akt pathway correlate in high-grade prostate cancer clinical samples.

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Bmi1 expression and activation of PI3K/Akt pathway correlate in high-gra...
(A) Representative immunohistochemical staining for Bmi1 and pAkt on adjacent sections of formalin-fixed, paraffin-embedded human prostate cancer specimens. Scale bar: 100 μm. (B) Immunohistochemical assessment of Bmi1 and pAkt expression status in 168 human prostate tumors categorized according to histological or clinical grade (see Table 1). Bmi1+pAkt+ tumors were associated with high Gleason scores (P < 0.001) and with advanced pathological stage (P = 0.002). (C) Immunohistochemical assessment of Bmi1 and pAkt expression status in 168 human prostate tumors categorized according to both histological and clinical grade (see Table 1). Bmi1+pAkt+ tumors were associated with worsening of both Gleason score and pathological stage (i.e., Gleason ≥ 8 and pT3; P = 0.001).