An IKK a –E2F1–BMI1 cascade activated by infiltrating B cells controls prostate regeneration and tumor recurrence

Androgen-deprived prostate cancer (PCa) is infiltrated by B lymphocytes that produce cytokines that activate I k B kinase a (IKK a ) to accelerate the emergence of castration-resistant tumors. We now demonstrate that infiltrating B lymphocytes and IKK a are also required for androgen-dependent expansion of epithelial progenitors responsible for prostate regeneration. In these cells and in PCa cells, IKK a 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 IKK a –BMI1 pathway is also activated in human PCa.