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

Wei Yu Chen; Yu Ching Wen; Shian Ren Lin; Hsiu Lien Yeh; Kuo Ching Jiang; Wei Hao Chen; Yow Sien Lin; Qingfu Zhang; Phui Ly Liew; Michael Hsiao; Jiaoti Huang; Yen Nien Liu

doi:10.1038/s42003-020-01549-1

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

Wei Yu Chen, Yu Ching Wen, Shian Ren Lin, Hsiu Lien Yeh, Kuo Ching Jiang, Wei Hao Chen, Yow Sien Lin, Qingfu Zhang, Phui Ly Liew, Michael Hsiao, Jiaoti Huang, Yen Nien Liu

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

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.

Original language	English
Article number	22
Journal	Communications Biology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s42003-020-01549-1
Publication status	Published - Dec 2021

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Medicine (miscellaneous)
Medicine(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s42003-020-01549-1

Cite this

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. (2021). Nerve growth factor interacts with CHRM4 and promotes neuroendocrine differentiation of prostate cancer and castration resistance. Communications Biology, 4(1), Article 22. https://doi.org/10.1038/s42003-020-01549-1

@article{01240d32b2b94e72bb86c4edf91be746,

title = "Nerve growth factor interacts with CHRM4 and promotes neuroendocrine differentiation of prostate cancer and castration resistance",

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.",

author = "Chen, {Wei Yu} and Wen, {Yu Ching} and Lin, {Shian Ren} and Yeh, {Hsiu Lien} and Jiang, {Kuo Ching} and Chen, {Wei Hao} and Lin, {Yow Sien} and Qingfu Zhang and Liew, {Phui Ly} and Michael Hsiao and Jiaoti Huang and Liu, {Yen Nien}",

note = "Funding Information: This work was jointly supported by grants from the Ministry of Science and Technology of Taiwan (MOST108-2320-B-038-047) to W.-Y.C. and (MOST108-2628-B-038-001 and MOST109-2326-B-038-001-MY3) to Y.-N.L., Taipei Medical University-Wan Fang Hospital (108TMU-WFH-03) to W.-Y.C., and the National Health Research Institute of Taiwan (NHRI-EX109-10702BI) to Y.-N.L. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2021",

month = dec,

doi = "10.1038/s42003-020-01549-1",

language = "English",

volume = "4",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer Nature",

number = "1",

}

TY - JOUR

T1 - Nerve growth factor interacts with CHRM4 and promotes neuroendocrine differentiation of prostate cancer and castration resistance

AU - Chen, Wei Yu

AU - Wen, Yu Ching

AU - Lin, Shian Ren

AU - Yeh, Hsiu Lien

AU - Jiang, Kuo Ching

AU - Chen, Wei Hao

AU - Lin, Yow Sien

AU - Zhang, Qingfu

AU - Liew, Phui Ly

AU - Hsiao, Michael

AU - Huang, Jiaoti

AU - Liu, Yen Nien

N1 - Funding Information: This work was jointly supported by grants from the Ministry of Science and Technology of Taiwan (MOST108-2320-B-038-047) to W.-Y.C. and (MOST108-2628-B-038-001 and MOST109-2326-B-038-001-MY3) to Y.-N.L., Taipei Medical University-Wan Fang Hospital (108TMU-WFH-03) to W.-Y.C., and the National Health Research Institute of Taiwan (NHRI-EX109-10702BI) to Y.-N.L. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85098617297&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85098617297&partnerID=8YFLogxK

U2 - 10.1038/s42003-020-01549-1

DO - 10.1038/s42003-020-01549-1

M3 - Article

C2 - 33398073

AN - SCOPUS:85098617297

SN - 2399-3642

VL - 4

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 22

ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this