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 4

The Pten/PI3K/pAkt axis modulates Bmi1 phosphorylation.

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The Pten/PI3K/pAkt axis modulates Bmi1 phosphorylation. (A) Western blot...
(A) Western blot analysis and relative quantification of pBmi1/Bmi1 ratio in Jurkat, PC3, and LNCaP Pten-deficient pAkt-high cells and in MCF7, DU145, and U2OS Pten-proficient pAkt-low cells. (B) Western blot showed that retrovirus-induced expression of PTEN in LNCaP cells inhibited pAkt and pBmi1. (C) Bmi1 phosphorylation was positively modulated by pAkt level. Bmi1 phosphorylation and pAkt and PTEN status in DU145, PC3, LNCaP, and PNT1a prostate cell lines either left untreated or treated with 5 μM Akt inhibitor VIII (isozyme selective, Akt-1/2; Calbiochem) for 12 hours and refreshed 2 hours prior to lysis. pBmi1/Bmi1 ratios, quantified using ImageJ, are indicated within blots (2 separate experiments shown). The 3 lower panels corresponded to experiment 2. Phosphorylation status of the Akt substrate GSK-3β (pSer9) is shown as a control for Akt activity. Tubulin was used as a loading control.