Nerve growth factor interacts with CHRM4 and promotes neuroendocrine differentiation of prostate cancer and castration resistance.

Journal Article (Journal Article)

Nerve growth factor (NGF) contributes to the progression of malignancy. However, the functional role and regulatory mechanisms of NGF in the development of neuroendocrine prostate cancer (NEPC) are unclear. Here, we show that an androgen-deprivation therapy (ADT)-stimulated transcription factor, ZBTB46, upregulated NGF via ZBTB46 mediated-transcriptional activation of NGF. NGF regulates NEPC differentiation by physically interacting with a G-protein-coupled receptor, cholinergic receptor muscarinic 4 (CHRM4), after ADT. Pharmacologic NGF blockade and NGF knockdown markedly inhibited CHRM4-mediated NEPC differentiation and AKT-MYCN signaling activation. CHRM4 stimulation was associated with ADT resistance and was significantly correlated with increased NGF in high-grade and small-cell neuroendocrine prostate cancer (SCNC) patient samples. Our results reveal a role of the NGF in the development of NEPC that is linked to ZBTB46 upregulation and CHRM4 accumulation. Our study provides evidence that the NGF-CHRM4 axis has potential to be considered as a therapeutic target to impair NEPC progression.

Full Text

Duke Authors

Cited Authors

  • Chen, W-Y; Wen, Y-C; Lin, S-R; Yeh, H-L; Jiang, K-C; Chen, W-H; Lin, Y-S; Zhang, Q; Liew, P-L; Hsiao, M; Huang, J; Liu, Y-N

Published Date

  • January 4, 2021

Published In

Volume / Issue

  • 4 / 1

Start / End Page

  • 22 -

PubMed ID

  • 33398073

Pubmed Central ID

  • PMC7782543

Electronic International Standard Serial Number (EISSN)

  • 2399-3642

Digital Object Identifier (DOI)

  • 10.1038/s42003-020-01549-1


  • eng

Conference Location

  • England