br Wei Yu Chena b
Wei-Yu Chena,b, Tao Zengc, Yu-Chng Wend,e, Hsiu-Lien Yehf, Kuo-Ching Jiangg, Wei-Hao Cheng, Qingfu Zhangh, Jiaoti Huangi, Yen-Nien Liug,j,∗ a Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
b Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
c Department of Urology, The People's Hospital of Jiangxi Province, Nanchang, China
d Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
e Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
f Institute of Information System and Applications, National Tsing Hua University, Hsinchu, Taiwan
g Graduate Institute of Molecular Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
h Department of Pathology, The First Aﬃliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China
i Department of Pathology, Duke University Medical Center, Durham, NC, USA
j TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
Androgen deprivation therapy (ADT)
Neuroendocrine prostate cancer (NEPC)
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 in-completely understood. Herein, we show that an immunocyte Chloramphenicol 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 as-sociated with NE prostate cancer (NEPC) diﬀerentiation. In addition, ZBTB46 acts as a transcriptional coacti-vator 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.
The androgen receptor (AR), a nuclear receptor that is activated by binding to androgens , promotes the development of prostate cancer . Although traditional AR-targeted therapies are initially eﬀective, most tumors progress to hormone-refractory prostate cancer or castra-tion-resistant prostate cancer (CRPC) within a few years . CRPC patients are commonly treated with androgen deprivation therapy
(ADT); however, ADT accelerates neuroendocrine (NE) diﬀerentiation with an increased anti-apoptotic stimulus that enables tumor resistance to the AR-targeted therapies [4–7]. NE diﬀerentiation is mainly ex-pressed in high-grade and high-stage prostate cancer, particularly in CRPC after ADT [8–11]. An emerging resistant phenotype is NE pros-tate cancer (NEPC) or small-cell NE prostate cancer (SCNC) character-ized by the absence of AR expression or loss of AR signaling [12–14]. The prognosis for NEPC is poor owing to the lack of relevant biomarkers
Abbreviations: ADT, Androgen deprivation therapy; ChIP, Chromatin immunoprecipitation; COX1, Cyclooxygenase 1; CHGA, Chromogranin A; CHGB, Chromogranin B; CRPC, Castration-resistant prostate cancer; CSS, Charcoal-stripped serum; DC, Dendritic cell; EMT, Epithelial-to-mesenchymal transition; ENO2, Enolase 2; GSEA, Gene set enrichment analysis; IF, Immunofluorescence; IHC, Immunohistochemical; NE, Neuroendocrine; NEPC, Neuroendocrine prostate cancer; PTGS1, Prostaglandin-endoperoxide synthase 1; SCNC, Small-cell neuroendocrine prostate cancer; SPDEF, SAM pointed domain containing ETS transcription factor; SYP, Synaptophysin; TCGA, The Cancer Genome Atlas; ZBTB46, Zinc finger and BTB domain containing 46
∗ Corresponding author. Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan. E-mail address: [email protected] (Y.-N. Liu).
and therapeutic approaches that target NEPC patients [7,15]. In-creasing attention has been focused on the NE diﬀerentiation of pros-tate cancer [16–19]; however, the mechanisms remain considerably less well understood.