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

Abstract

Androgen-deprived prostate cancer (PCa) is infiltrated by B lymphocytes that produce cytokines that activate IkB kinase a (IKKa) to accelerate the emergence of castrationresistant tumors. We now demonstrate that infiltrating B lymphocytes and IKKa are also required for androgendependent expansion of epithelial progenitors responsible for prostate regeneration. In these cells and in PCa cells, IKKa 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 IKKa-BMI1 pathway is also activated in human PCa. © 2013 by Cold Spring Harbor Laboratory Press.