Targeting Wnt/EZH2/microRNA-708 signaling pathway inhibits neuroendocrine differentiation in prostate cancer

Jingxuan Shan, Mariam A. Al-Muftah, Moza K. Al-Kowari, Sirin W.J. Abuaqel, Khalid Al-Rumaihi, Issam Al-Bozom, Pu Li, Lotfi Chouchane

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Prostate cancer (PC) castration resistance has been linked to the differentiation of PC luminal cells into hormone-refractory neuroendocrine (NE) cells. However, the molecular mechanisms controlling the emergence of lethal NE prostate cancer (NEPC) remain unclear. The present study aimed to investigate the mechanisms underlying the transition from prostate adenocarcinoma to NEPC. The microRNA miR-708 was involved in NE differentiation and was downregulated in NEPC cells and tumor specimens. miR-708 targeted Sestrin-3 to inhibit Forkhead Box O1 (FOXO1) phosphorylation, resulting in apoptosis of prostate adenocarcinoma cells and AKT-inactivated NEPC cells, the latter of which was consistent with the progression of tumor xenografts in mice under miR-708 treatment. In silico analysis of PC and NEPC tumor specimens suggested that the polycomb repressive complex subunit Enhancer of zeste homolog 2 (EZH2) was particularly overexpressed in NEPC. Notably, EZH2 bound to the miR-708 promoter and induced its silencing in NEPC. Inhibition of EZH2 prevented NE differentiation of PC cells. EZH2 expression was regulated by both Cyclin Dependent Kinase 1 (CDK1) and Wnt signaling. Silencing transcription factor 4 (TCF4), as a key protein in Wnt signaling, prevented NEPC formation. These results provide a molecular basis for the roles of miR-708 and EZH2 in NE differentiation in PC and highlight a new paradigm in NEPC formation and survival.

Original languageEnglish
Article number139
JournalCell Death Discovery
Volume5
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Fingerprint

MicroRNAs
Prostatic Neoplasms
Enhancer of Zeste Homolog 2 Protein
Prostate
Adenocarcinoma
Wnt Proteins
CDC2 Protein Kinase
Neoplasms
Neuroendocrine Cells
Castration
Heterografts
Computer Simulation
Transcription Factors
Down-Regulation

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Targeting Wnt/EZH2/microRNA-708 signaling pathway inhibits neuroendocrine differentiation in prostate cancer. / Shan, Jingxuan; Al-Muftah, Mariam A.; Al-Kowari, Moza K.; Abuaqel, Sirin W.J.; Al-Rumaihi, Khalid; Al-Bozom, Issam; Li, Pu; Chouchane, Lotfi.

In: Cell Death Discovery, Vol. 5, No. 1, 139, 01.12.2019.

Research output: Contribution to journalArticle

@article{4d29c3828af843d78439112c0c2c82ff,
title = "Targeting Wnt/EZH2/microRNA-708 signaling pathway inhibits neuroendocrine differentiation in prostate cancer",
abstract = "Prostate cancer (PC) castration resistance has been linked to the differentiation of PC luminal cells into hormone-refractory neuroendocrine (NE) cells. However, the molecular mechanisms controlling the emergence of lethal NE prostate cancer (NEPC) remain unclear. The present study aimed to investigate the mechanisms underlying the transition from prostate adenocarcinoma to NEPC. The microRNA miR-708 was involved in NE differentiation and was downregulated in NEPC cells and tumor specimens. miR-708 targeted Sestrin-3 to inhibit Forkhead Box O1 (FOXO1) phosphorylation, resulting in apoptosis of prostate adenocarcinoma cells and AKT-inactivated NEPC cells, the latter of which was consistent with the progression of tumor xenografts in mice under miR-708 treatment. In silico analysis of PC and NEPC tumor specimens suggested that the polycomb repressive complex subunit Enhancer of zeste homolog 2 (EZH2) was particularly overexpressed in NEPC. Notably, EZH2 bound to the miR-708 promoter and induced its silencing in NEPC. Inhibition of EZH2 prevented NE differentiation of PC cells. EZH2 expression was regulated by both Cyclin Dependent Kinase 1 (CDK1) and Wnt signaling. Silencing transcription factor 4 (TCF4), as a key protein in Wnt signaling, prevented NEPC formation. These results provide a molecular basis for the roles of miR-708 and EZH2 in NE differentiation in PC and highlight a new paradigm in NEPC formation and survival.",
author = "Jingxuan Shan and Al-Muftah, {Mariam A.} and Al-Kowari, {Moza K.} and Abuaqel, {Sirin W.J.} and Khalid Al-Rumaihi and Issam Al-Bozom and Pu Li and Lotfi Chouchane",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41420-019-0218-y",
language = "English",
volume = "5",
journal = "Cell Death Discovery",
issn = "2058-7716",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Targeting Wnt/EZH2/microRNA-708 signaling pathway inhibits neuroendocrine differentiation in prostate cancer

AU - Shan, Jingxuan

AU - Al-Muftah, Mariam A.

AU - Al-Kowari, Moza K.

AU - Abuaqel, Sirin W.J.

AU - Al-Rumaihi, Khalid

AU - Al-Bozom, Issam

AU - Li, Pu

AU - Chouchane, Lotfi

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Prostate cancer (PC) castration resistance has been linked to the differentiation of PC luminal cells into hormone-refractory neuroendocrine (NE) cells. However, the molecular mechanisms controlling the emergence of lethal NE prostate cancer (NEPC) remain unclear. The present study aimed to investigate the mechanisms underlying the transition from prostate adenocarcinoma to NEPC. The microRNA miR-708 was involved in NE differentiation and was downregulated in NEPC cells and tumor specimens. miR-708 targeted Sestrin-3 to inhibit Forkhead Box O1 (FOXO1) phosphorylation, resulting in apoptosis of prostate adenocarcinoma cells and AKT-inactivated NEPC cells, the latter of which was consistent with the progression of tumor xenografts in mice under miR-708 treatment. In silico analysis of PC and NEPC tumor specimens suggested that the polycomb repressive complex subunit Enhancer of zeste homolog 2 (EZH2) was particularly overexpressed in NEPC. Notably, EZH2 bound to the miR-708 promoter and induced its silencing in NEPC. Inhibition of EZH2 prevented NE differentiation of PC cells. EZH2 expression was regulated by both Cyclin Dependent Kinase 1 (CDK1) and Wnt signaling. Silencing transcription factor 4 (TCF4), as a key protein in Wnt signaling, prevented NEPC formation. These results provide a molecular basis for the roles of miR-708 and EZH2 in NE differentiation in PC and highlight a new paradigm in NEPC formation and survival.

AB - Prostate cancer (PC) castration resistance has been linked to the differentiation of PC luminal cells into hormone-refractory neuroendocrine (NE) cells. However, the molecular mechanisms controlling the emergence of lethal NE prostate cancer (NEPC) remain unclear. The present study aimed to investigate the mechanisms underlying the transition from prostate adenocarcinoma to NEPC. The microRNA miR-708 was involved in NE differentiation and was downregulated in NEPC cells and tumor specimens. miR-708 targeted Sestrin-3 to inhibit Forkhead Box O1 (FOXO1) phosphorylation, resulting in apoptosis of prostate adenocarcinoma cells and AKT-inactivated NEPC cells, the latter of which was consistent with the progression of tumor xenografts in mice under miR-708 treatment. In silico analysis of PC and NEPC tumor specimens suggested that the polycomb repressive complex subunit Enhancer of zeste homolog 2 (EZH2) was particularly overexpressed in NEPC. Notably, EZH2 bound to the miR-708 promoter and induced its silencing in NEPC. Inhibition of EZH2 prevented NE differentiation of PC cells. EZH2 expression was regulated by both Cyclin Dependent Kinase 1 (CDK1) and Wnt signaling. Silencing transcription factor 4 (TCF4), as a key protein in Wnt signaling, prevented NEPC formation. These results provide a molecular basis for the roles of miR-708 and EZH2 in NE differentiation in PC and highlight a new paradigm in NEPC formation and survival.

UR - http://www.scopus.com/inward/record.url?scp=85073194730&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073194730&partnerID=8YFLogxK

U2 - 10.1038/s41420-019-0218-y

DO - 10.1038/s41420-019-0218-y

M3 - Article

AN - SCOPUS:85073194730

VL - 5

JO - Cell Death Discovery

JF - Cell Death Discovery

SN - 2058-7716

IS - 1

M1 - 139

ER -