Abstract
Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.
Highlights
Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly overexpressed in diverse human carcinomas and contributes to hallmarks of the cancer cell, including epithelial-mesenchymal transition (EMT), stemness, anticancer drug resistance, epigenetic reprogramming, and immune evasion[13,14,15,16]
We show that MUC1-C (i) activates the BRN2 pathway in association with induction of MYCN, EZH2, and NE markers linked to neuroendocrine prostate cancer (NEPC) progression, (ii) suppresses the p53 pathway, (iii) induces the OCT4, SOX2, KLF4 and MYC (OSKM) pluripotency factors and (iv) drives stemness
C4-2B cells were selected for long-term culture in phenol red-free medium and charcoal-stripped serum to assess the potential for MUC1-C involvement in supporting androgen-independent (AI) growth
Summary
Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly overexpressed in diverse human carcinomas and contributes to hallmarks of the cancer cell, including EMT, stemness, anticancer drug resistance, epigenetic reprogramming, and immune evasion[13,14,15,16]. MUC1 expression has been linked to (i) early biochemical failure and PC-related death[20], and (ii) bone metastases in CRPC21. These findings have supported the potential importance of MUC1 in advanced PC; there is no known link between MUC1 and PC progression. The present studies demonstrate that MUC1-C suppresses AR axis signaling in PC cells and drives expression of the BRN2 neural TF by a previously unreported MYC-dependent mechanism. We show that MUC1-C (i) activates the BRN2 pathway in association with induction of MYCN, EZH2, and NE markers linked to NEPC progression, (ii) suppresses the p53 pathway, (iii) induces the OCT4, SOX2, KLF4 and MYC (OSKM) pluripotency factors and (iv) drives stemness. In support of clinical relevance, we report that targeting MUC1-C in vitro and in PC tumor xenograft models inhibits BRN2 signaling, the NE phenotype, self-renewal capacity and tumorigenicity
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