PRDM16 Regulates Prostate Cancer Cell Dormancy and Prevents Bone Metastatic Outgrowth
Understanding dormancy in prostate cancer (PCa) is challenging due to model availability. Here, using murine and human PCa 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-Seq analysis revealed that the transcription factor PR domain containing 16 (PRDM16) was commonly upregulated in dormant PCa cells compared to controls. Further, bone marrow disseminated tumor PCa cells from primary orthotopic tumors were largely positive for PRDM16. Genetic ablation and forced ectopic expression supported a role for PRDM16 in maintaining PCa dormancy in vitro and in vivo. Clinically, PRDM16 negatively correlated with disease recurrence, and PRDM16 negatively correlated with the E2F cell cycle program in disseminated tumor cells derived from PCa patient bone marrow. Gene enrichment and characterization studies implicated PRDM16 as a regulator of metabolic and cell cycle pathways. ChIP-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 PCa. Overall design: RNASeq analysis of different PCa cell lines in active, dormant, and reawakened conditions after short in vitro culture 48 hours in dormancy and 24 hours in reawakened conditions.