MUC1-C Activates the BAF (mSWI/SNF) Complex in Prostate Cancer Stem Cells

Cancer Res. 2021 Feb 15;81(4):1111-1122. doi: 10.1158/0008-5472.CAN-20-2588. Epub 2020 Dec 15.


The Brg/Brahma-associated factor (BAF, mSWI/SNF) chromatin remodeling complex is of importance in development and has been linked to prostate oncogenesis. The oncogenic MUC1-C protein promotes lineage plasticity in the progression of neuroendocrine prostate cancer (NEPC), however, there is no known association between MUC1-C and BAF. We report here that MUC1-C binds directly to the E2F1 transcription factor and that the MUC1-C→E2F1 pathway induces expression of embryonic stem cell-specific BAF (esBAF) components BRG1, ARID1A, BAF60a, BAF155, and BAF170 in castrate-resistant prostate cancer (CRPC) and NEPC cells. In concert with this previously unrecognized pathway, MUC1 was associated with increased expression of E2F1 and esBAF components in NEPC tumors as compared with CRPC, supporting involvement of MUC1-C in activating the E2F1→esBAF pathway with progression to NEPC. MUC1-C formed a nuclear complex with BAF and activated cancer stem cell (CSC) gene signatures and the core pluripotency factor gene network. The MUC1-C→E2F1→BAF pathway was necessary for induction of both the NOTCH1 effector of CSC function and the NANOG pluripotency factor, and collectively, this network drove CSC self-renewal. These findings indicate that MUC1-C promotes NEPC progression by integrating activation of E2F1 and esBAF with induction of NOTCH1, NANOG, and stemness. SIGNIFICANCE: These findings show that MUC1-C, which promotes prostate cancer progression, activates a novel pathway that drives the BAF remodeling complex, induces NOTCH1 and NANOG, and promotes self-renewal of prostate cancer stem cells.

Publication types

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

MeSH terms

  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Carcinoma, Neuroendocrine* / genetics
  • Carcinoma, Neuroendocrine* / metabolism
  • Carcinoma, Neuroendocrine* / pathology
  • Cell Self Renewal / genetics
  • Chromatin Assembly and Disassembly / genetics
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Male
  • Mucin-1 / physiology*
  • Multiprotein Complexes / genetics*
  • Multiprotein Complexes / metabolism
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / metabolism
  • Prostatic Neoplasms* / pathology
  • Protein Isoforms / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured


  • ARID1A protein, human
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • MUC1 protein, human
  • Mucin-1
  • Multiprotein Complexes
  • Nuclear Proteins
  • Protein Isoforms
  • SMARCC1 protein, human
  • SMARCC2 protein, human
  • SMARCD1 protein, human
  • Transcription Factors
  • SMARCA4 protein, human
  • DNA Helicases