Abstract
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.
Highlights
Nerve growth factor (NGF) contributes to the progression of malignancy
We found that patients post-androgen-deprivation therapy (ADT) had increased ZBTB46 and neuroendocrine marker levels but had decreased androgenresponsive gene expressions in this dataset (Supplementary Fig. 1a)
To study the regulatory mechanisms involved in ZBTB46 upregulation during neuroendocrine prostate cancer (NEPC) development, we examined relationships between ZBTB46 and activation of signatures of NEPCresponsive genes in The Cancer Genome Atlas (TCGA) prostate cancer dataset
Summary
Nerve growth factor (NGF) contributes to the progression of malignancy. the functional role and regulatory mechanisms of NGF in the development of neuroendocrine prostate cancer (NEPC) are unclear. Results showed that tissues expressing high levels of ZBTB46 were associated with an upregulated NEPC-responsive signature in the prostate cancer dataset by a gene set enrichment analysis (GSEA)[25] (Fig. 1a). Increased NGF mRNA levels were found to be dependent on ZBTB46, as ZBTB46-knockdown reduced NGF and neuroendocrine marker expressions in C4-2 and LNCaP cells, regardless of an ADT-mimicking condition (achieved using charcoal-stripped serum (CSS)-containing medium) (Fig. 1e, f).
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