MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

Nat Commun. 2020 Jan 17;11(1):338. doi: 10.1038/s41467-019-14219-6.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aurora Kinase A / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Carcinogenesis / genetics
  • Carcinoma, Neuroendocrine / genetics
  • Carcinoma, Neuroendocrine / metabolism*
  • Cell Line, Tumor
  • Disease Progression*
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Nude
  • Mucin-1 / genetics
  • Mucin-1 / metabolism*
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neoplastic Stem Cells / metabolism
  • Neuronal Plasticity / physiology*
  • Octamer Transcription Factor-3 / metabolism
  • POU Domain Factors / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Proto-Oncogene Proteins c-myc
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction
  • Synaptophysin / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • GKLF protein
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • MUC1 protein, human
  • MYC protein, human
  • MYCN protein, human
  • Mucin-1
  • N-Myc Proto-Oncogene Protein
  • Octamer Transcription Factor-3
  • POU Domain Factors
  • POU5F1 protein, human
  • Proto-Oncogene Proteins c-myc
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • SYP protein, human
  • Synaptophysin
  • Tumor Suppressor Protein p53
  • transcription factor Brn-2
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Aurora Kinase A