Androgen deprivation-induced ZBTB46-PTGS1 signaling promotes neuroendocrine differentiation of prostate cancer

Wei Yu Chen, Tao Zeng, Yu Chng Wen, Hsiu Lien Yeh, Kuo Ching Jiang, Wei Hao Chen, Qingfu Zhang, Jiaoti Huang, Yen Nien Liu

Research output: Contribution to journalArticle

Abstract

Androgen receptor (AR) targeting is an important therapeutic strategy for treating prostate cancer. Most tumors progress to castration-resistant prostate cancer (CRPC) and develop the neuroendocrine (NE) phenotype under androgen deprivation therapy (ADT). The molecular basis for NE transdifferentiation after ADT remains incompletely understood. Herein, we show that an immunocyte expression protein, ZBTB46, induces inflammatory response gene expression and contributes to NE differentiation of prostate cancer cells. We demonstrated a molecular mechanism whereby ZBTB46 can be regulated by the androgen-responsive gene, SPDEF, and is associated with NE prostate cancer (NEPC) differentiation. In addition, ZBTB46 acts as a transcriptional coactivator that binds to the promoter of prostaglandin-endoperoxide synthase 1 (PTGS1) and transcriptionally regulated PTGS1 levels. Overexpression of ZBTB46 decreases the sensitivity of the combination of enzalutamide and a PTGS1 inhibitor; however, knockdown of ZBTB46 sensitizes the PTGS1 inhibitor and reduces tumor malignancy. ZBTB46 is inversely correlated with SPDEF and is increased in higher tumor grades and small-cell NE prostate cancer (SCNC) patients, which are positively associated with PTGS1. Our findings suggest that the induction of ZBTB46 results in increased PTGS1 expression, which is associated with NEPC progression and linked to the dysregulation of the AR-SPDEF pathway.

LanguageEnglish
Pages35-46
Number of pages12
JournalCancer Letters
Volume440-441
DOIs
Publication statusPublished - Jan 1 2019

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Prostaglandin-Endoperoxide Synthases
Androgens
Prostatic Neoplasms
Cyclooxygenase Inhibitors
Androgen Receptors
Neoplasms
Neuroendocrine Cells
Castration
Therapeutics
Phenotype
Gene Expression
Genes
Proteins

Keywords

  • Androgen deprivation therapy (ADT)
  • Neuroendocrine prostate cancer (NEPC)
  • PTGS1
  • SPDEF
  • ZBTB46

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Androgen deprivation-induced ZBTB46-PTGS1 signaling promotes neuroendocrine differentiation of prostate cancer. / Chen, Wei Yu; Zeng, Tao; Wen, Yu Chng; Yeh, Hsiu Lien; Jiang, Kuo Ching; Chen, Wei Hao; Zhang, Qingfu; Huang, Jiaoti; Liu, Yen Nien.

In: Cancer Letters, Vol. 440-441, 01.01.2019, p. 35-46.

Research output: Contribution to journalArticle

Chen, Wei Yu ; Zeng, Tao ; Wen, Yu Chng ; Yeh, Hsiu Lien ; Jiang, Kuo Ching ; Chen, Wei Hao ; Zhang, Qingfu ; Huang, Jiaoti ; Liu, Yen Nien. / Androgen deprivation-induced ZBTB46-PTGS1 signaling promotes neuroendocrine differentiation of prostate cancer. In: Cancer Letters. 2019 ; Vol. 440-441. pp. 35-46.
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