title: 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.affiliation: Division of Molecular Genetics and Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Karim
authors.initials: K
authors.lastname: Nacerddine
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Beaudry
authors.forename: Vasudeva
authors.initials: V
authors.lastname: Ginjala
authors.forename: Bart
authors.initials: B
authors.lastname: Westerman
authors.forename: Francesca
authors.initials: F
authors.lastname: Mattiroli
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.forename: Henk
authors.initials: H
authors.lastname: van der Poel
authors.forename: Olga Balagué
authors.initials: OB
authors.lastname: Ponz
authors.forename: Colin
authors.initials: C
authors.lastname: Pritchard
authors.forename: Paulien
authors.initials: P
authors.lastname: Cornelissen-Steijger
authors.forename: John
authors.initials: J
authors.lastname: Zevenhoven
authors.forename: Ellen
authors.initials: E
authors.lastname: Tanger
authors.forename: Titia K
authors.initials: TK
authors.lastname: Sixma
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004789:Enzyme Activation; D042822:Genomic Instability; D057895:Haploinsufficiency; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D063150:Polycomb Repressive Complex 1; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C489421:Bmi1 protein, mouse; D006657:Histones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse