PRDM16 Regulates Prostate Cancer Cell Dormancy and Prevents Bone Metastatic Outgrowth.

Understanding dormancy in prostate cancer is challenging because of model availability. In this study, using murine and human prostate cancer cell lines, we generated a stress-induced model of dormancy in vitro and demonstrated that the phenotype could be sustained upon intrailiac artery delivery into the bone marrow microenvironment. RNA sequencing analysis revealed that the transcription factor positive regulatory domain-containing 16 (PRDM16) was commonly upregulated in dormant prostate cancer cells compared with controls. Furthermore, bone marrow-disseminated prostate cancer cells from primary orthotopic tumors were largely positive for PRDM16. Genetic ablation and forced ectopic expression supported a role for PRDM16 in maintaining prostate cancer dormancy in vitro and in vivo. Clinically, PRDM16 negatively correlated with disease recurrence and with the E2F cell-cycle program in disseminated tumor cells derived from the bone marrow of patients with prostate cancer. Gene enrichment and characterization studies implicated PRDM16 as a regulator of metabolic and cell-cycle pathways. Chromatin immunoprecipitation-qPCR further revealed that PRDM16 binds upstream of the promoter of RB1, a potent repressor of E2F activity. Overall, this study developed a straightforward method for inducing cancer cell dormancy and applied this approach to find that PRDM16 governs an intrinsic dormancy program in prostate cancer. SIGNIFICANCE: PRDM16 initiates a dormancy program in prostate cancer cells that is sustained in the bone marrow microenvironment, highlighting PRDM16 as a potential biomarker for relapse and target for eliminating dormant cancer cells.