MUC1-C INTEGRATES CHRONIC TYPE II INTERFERON SIGNALING WITH CHROMATIN REMODELING PATHWAYS IN IMMUNOSUPPRESSION OF PROSTATE CANCER

The cancer stem cell (CSC) state is intimately associated with suppression of the immune tumor microenvironment (TME). The oncogenic MUC1-C protein drives dedifferentiation of castrate resistant prostate cancer (CRPC) CSCs in association with induction of the BAF, NuRD and PBAF chromatin remodeling complexes. The present work demonstrates that MUC1-C is necessary for expression of IFNGR1 and activation of the type II interferon-gamma (IFN-?? pathway in CRPC cells. We show that the MUC1-C?ARID1A/BAF pathway induces IFNGR1 transcription and that MUC1-C?NuRD signaling suppresses FBXW7 in stabilizing the IFNGR1 protein. MUC1-C and NuRD were also necessary for expression of the downstream STAT1 and IRF1 transcription factors. Additionally and in contrast, our results demonstrate that MUC1-C and the PBRM1/PBAF pathway are necessary for IRF1-induced expression of (i) IDO1, WARS and PTGES, which metabolically suppress the immune TME, and (ii) the ISG15 and SERPINB9 inhibitors of T cell function. Of translational relevance, we show that MUC1 associates with expression of IFNGR1, STAT1 and IRF1, as well as the downstream IDO1, WARS, PTGES, ISG15 and SERPINB9 immunosuppressive effectors in CRPC tumors. Consistent with these results, MUC1 associates with immune cell-depleted “cold” CRPC TMEs. These findings demonstrate that MUC1-C integrates chronic activation of the type II IFN-G pathway with induction of chromatin remodeling complexes in linking CSC dedifferentiation and immune evasion. Overall design: DU-145 cells stably expressing a tet-MUCshRNA vector were treated with vehicle or DOX for 7 days were stimulated with 10 ng/ml IFN-g for 24 hours.. Total RNA from cells cultured in triplicates was isolated and used for library preparation.