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    3.7. ZBTB46 is inversely correlated with SPDEF and positively correlated with PTGS1 in prostate cancer patients receiving ADT
    To study the relationships among ZBTB46, SPDEF, and PTGS1, we analyzed a prostate cancer TMA collected from the Department of Pathology, Duke University School of Medicine (NC, USA). The IHC results showed a reverse correlation between ZBTB46 and SPDEF and a positive correlation between ZBTB46 and PTGS1 (Fig. 7A). In addition, the high-grade tumor and small-cell NE prostate cancer (SCNC) samples had greater abundances of ZBTB46 and PTGS1 and a lower abundance of SPDEF (Fig. 7B and Supplementary Fig. S6A). Quantitative co-IF 
    staining of the TMA showed that PTGS1 expression was restricted to the NE-like (CHGA-positive) tumor Doxorubicin (Fig. 7C). Moreover, the ZBTB46 abundance was found to be significantly associated with an upregulated NEPC response signature [14] as confirmed by a GSEA (Fig. 7D). Fur-thermore, the mean expression correction was validated from the Taylor and TCGA prostate cancer datasets. The results show that ZBTB46 was positively correlated with the NE markers (SYP, CHGA, CHGB, and ENO2) and PTGS1 expression and inversely correlated with the SPDEF and AR-responsive genes (FKBP5, NKX3-1, and KLK3) ac-cording to a Pearson coefficient correction analysis (Fig. 7E and Supplementary Fig. S6B). These results indeed support the induction of ZBTB46 and PTGS1 and a reduction in SPDEF as being associated with NEPC differentiation. We extended our analysis to prostate cancer
    Fig. 7. ZBTB46 is positively correlated with NE markers and PTGS1 in prostate cancer patients. (A) Representative images of IHC staining of consecutive sections of a prostate cancer tissue microarray (TMA) from the Duke University School of Medicine. Scale bars, 100 μm. (B) IHC staining for ZBTB46, PTGS1, and SPDEF in prostate cancer TMA sections containing normal tissues (n = 16), adenocarcinomas with a Gleason score of ≤7 (n = 71), adenocarcinomas with a Gleason score of ≥8 (n = 29), and small-cell NE prostate cancers (SCNCs) (n = 8) from the Duke University School of Medicine. Scale bars, 100 μm. (C) IF staining of the TMA showing coexpression of PTGS1 and CHGA in the same tumor cells. Scale bars, 50 μm. (D) GSEA of TCGA prostate datasets showed that higher ZBTB46 expression of prostate tissues was associated with an NEPC response signaling gene set. (E) Pearson correlation analysis of ZBTB46 with SYP mRNAs in clinical tissue samples from the Taylor prostate cancer dataset. (F and G) IHC staining of ZBTB46, PTGS1 and SPDEF (F) and analysis (G) of nuclear ZBTB46 and SPDEF and cytoplasmic PTGS1 in prostate cancer tissue sections from patients before and after ADT. n = 21 samples from Taipei Medical University-Wan Fang Hospital. Scale bars, 100 μm. Statistical analysis by two-tailed Student's t-test. (H) Proposed model for reducing the activity of AR signaling by ADT or AR inhibitors, which activates ZBTB46, facilitating the development of malignant progression and NE differentiation of prostate cancer cells through the activation of ZBTB46 and PTGS1 by loss of SPDEF.
    samples comprising tissue specimens from 21 prostate cancer patients treated before and after ADT collected from Taipei Medical University-Wan Fang Hospital (Taiwan). We found that both nuclear ZBTB46 and cytoplasmic PTGS1 were increased and that nuclear SPDEF was reduced in prostate tumors from the patients who had received ADT compared 
    with the same patients before ADT treatment (Fig. 7F and G). These results suggest that inhibition of AR signaling by ADT may cause a reduction in SPDEF and activation of the ZBTB46-promoting oncogenic signaling pathway components that induce PTGS1 abundance in a subset of patients with aggressive prostate cancer (Fig. 7H).
    4. Discussion
    In this study, we investigated the gene-regulatory networks that control prostate cancer reprogramming to NEPC and identified novel roles involving the ZBTB46 tumor promoter. We propose a role for ZBTB46 in NEPC progression that is mechanistically linked to the dysregulation of AR signaling pathways through the inactivation of tumor-suppressive SPDEF and activation of PTGS1. We verified that the ZBTB46 oncogenic network potentially regulates PTGS1 expression, is involved in NEPC differentiation, and supports its important pathogenic role in prostate cancer progression. ZBTB46-directed tumorigenesis emerged here as a major determinant of unfavorable outcomes in pa-tients with prostate cancer, and it was associated with the repression of SPDFE. Loss of SPDEF was shown to be involved in metastatic prostate cancer [40]. We demonstrated that SPDEF is the upstream factor that directly regulates ZBTB46. ADT-reduced SPDEF is the mechanism en-hancing ZBTB46 upregulation. The aberrant increases in ZBTB46 levels support multiple malignant progressions in prostate cancer, including enhanced cell proliferation, metastasis, and NEPC differentiation com-petency.