Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer
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
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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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 1

Bmi1 cooperates with PTEN haploinsufficiency in prostate cancer progression.

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Bmi1 cooperates with PTEN haploinsufficiency in prostate cancer progress...
(A) Schematic representation of the ROSA26 Lox-STOP-Lox Bmi1 allele (Bmi1LSL). (B) PIN- and carcinoma-free mice at the indicated ages. n = 29 (PbCre4); 36 (PbCre4;Bmi1LSL); 26 (PbCre4;PtenloxP/+); 24 (PbCre4;Bmi1LSL;PtenloxP/+). (C) Prostate histopathology of 1-year-old animals. PbCre4 controls (n = 21) appeared mostly normal. PbCre4;Bmi1LSL (n = 25) and PbCre4;PtenloxP/+ (n = 19) mice developed atypical hyperplasia (AH) and PIN lesions with incomplete penetrance, whereas only PbCre4;Bmi1LSL;PtenloxP/+ mice (n = 16) developed prostate adenocarcinoma. (D–G) H&E-stained prostate sections. (D) Normal epithelium in PbCre4 controls. (E) PIN lesion (asterisk) in PbCre4;Bmi1LSL mice. (F) PIN lesion (asterisk) in PbCre4;PtenloxP/+ mice. (G) Adenocarcinoma in PbCre4;Bmi1LSL;PtenloxP/+ animals. Black arrowhead, mitotic figure; white arrowheads, blood vessels. Insets are enlarged 5-fold. (H–O) Immunohistochemical expression analysis of Bmi1-phosphorylated Akt (H–K) and pAkt (S473) (L–O). Scale bars: 100 μm.