An IKKα-E2F1-BMI1 cascade activated by infiltrating B cells controls prostate regeneration and tumor recurrence

• Published in: Genes & development 2013-07, Vol.27 (13), p.1435-1440
• Main Authors: Ammirante, Massimo, Kuraishy, Ali I, Shalapour, Shabnam, Strasner, Amy, Ramirez-Sanchez, Claudia, Zhang, Weizhou, Shabaik, Ahmed, Karin, Michael
• Format: Article
• Language: English
• Subjects: Androgens - pharmacology; Animals; B-Lymphocytes - physiology; Cells, Cultured; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; Gene Expression Regulation, Developmental - drug effects; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Male; Mice; Neoplasm Recurrence, Local - physiopathology; Orchiectomy; Polycomb Repressive Complex 1 - genetics; Polycomb Repressive Complex 1 - metabolism; Prostate - drug effects; Prostate - physiopathology; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Regeneration; Research Communication
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.220202.113

Androgen-deprived prostate cancer (PCa) is infiltrated by B lymphocytes that produce cytokines that activate IκB kinase α (IKKα) to accelerate the emergence of castration-resistant tumors. We now demonstrate that infiltrating B lymphocytes and IKKα are also required for androgen-dependent expansion of epithelial progenitors responsible for prostate regeneration. In these cells and in PCa cells, IKKα phosphorylates transcription factor E2F1 on a site that promotes its nuclear translocation, association with the coactivator CBP, and recruitment to critical genomic targets that include Bmi1, a key regulator of normal and cancerous prostate stem cell renewal. The IKKα-BMI1 pathway is also activated in human PCa.