DKK1

Overview

DKK1 (Dickkopf WNT Signaling Pathway Inhibitor 1) encodes a secreted inhibitor of the canonical WNT/β-catenin signaling pathway. In cancer, DKK1 acts as a context-dependent tumor suppressor (inhibiting WNT-driven growth) or a promoter of invasion and immune evasion. In the context of neuroendocrine prostate cancer (CRPC-NE), DKK1 was identified as an EZH2-repressed WNT-pathway target that is significantly downregulated relative to castration-resistant adenocarcinoma.

Alterations observed in the corpus

  • Transcriptional downregulation of DKK1 in CRPC-NE vs. CRPC-Adeno (P = 0.0002, Wilcoxon test) as part of the PRC2/EZH2 target gene repression program. DKK1 was among the most significantly down-regulated WNT-pathway antagonists in CRPC-NE. PMID:26855148

Cancer types (linked)

  • PRAD (castration-resistant, neuroendocrine subtype): DKK1 mRNA significantly lower in CRPC-NE than CRPC-Adeno (P = 0.0002, Wilcoxon); repression linked to EZH2 overexpression and PRC2 activity in CRPC-NE. Cohort: 114 metastatic biopsies, 81 patients (nepc_wcm_2016). PMID:26855148

Co-occurrence and mutual exclusivity

  • DKK1 downregulation co-occurs with EZH2 overexpression (mRNA 2× higher in CRPC-NE, P < 10⁻⁶) and NKD1 downregulation in the CRPC-NE epigenetic program. EZH2 inhibitor GSK343 preferentially reduced viability of NCI-H660 (NE) cells and partially reversed CRPC-NE gene expression. PMID:26855148

Therapeutic relevance

  • DKK1 repression in CRPC-NE is mechanistically downstream of EZH2 overactivity. EZH2 inhibition (GSK343) preferentially killed CRPC-NE cells in vitro and down-regulated CRPC-NE-associated transcripts, suggesting EZH2 inhibitors as a candidate strategy to reverse the epigenetic repression of DKK1 and other WNT antagonists in CRPC-NE. PMID:26855148

Open questions

  • Whether DKK1 repression in CRPC-NE is a causally relevant event promoting Wnt-dependent survival/invasion or a passenger consequence of global EZH2 hyperactivation is not resolved. Functional rescue experiments are needed. PMID:26855148

Sources

  • PMID:26855148 — Beltran et al. (2016), molecular characterization of 114 metastatic CRPC biopsies (nepc_wcm_2016), EZH2/PRC2 epigenetic program in CRPC-NE.

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