Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer

Abstract

The Wnt signaling pathway is of paramount importance for development and disease. However, the tissue-specific regulation of Wnt pathway activity remains incompletely understood. Here we identify FOXB2, an uncharacterized forkhead box family transcription factor, as a potent activator of Wnt signaling in normal and cancer cells. Mechanistically, FOXB2 induces multiple Wnt ligands, including WNT7B, which increases TCF/LEF-dependent transcription without activating Wnt coreceptor LRP6 or β-catenin. Proximity ligation and functional complementation assays identified several transcription regulators, including YY1, JUN, and DDX5, as cofactors required for FOXB2-dependent pathway activation. Although FOXB2 expression is limited in adults, it is induced in select cancers, particularly advanced prostate cancer. RNA-seq data analysis suggests that FOXB2/WNT7B expression in prostate cancer is associated with a transcriptional program that favors neuronal differentiation and decreases recurrence-free survival. Consistently, FOXB2 controls Wnt signaling and neuroendocrine differentiation of prostate cancer cell lines. Our results suggest that FOXB2 is a tissue-specific Wnt activator that promotes the malignant transformation of prostate cancer.

hPCL3S promotes proliferation and migration of androgen-independent prostate cancer cells

“…Validation by RT-qPCR analyses demonstrated that whereas it is not expressed in the parental LNCaP bulk cell population, FAM184A is highly up-regulated in the clones obtained after transfection with the empty expression vector ( Figure 12A). A similar "spontaneous" neuroendocrine transdifferentiation of LNCaP has been described in a study addressing the role of the Wnt activator FOXB2 after stable transfection in LNCaP of a control empty pcDNA3 vector followed by G418 selection [5]. In close agreement with the RNA-Seq data, overexpression of hPCL3S in LNCaP clone 12 strongly repressed the expression of FAM184A and even to a very low level as compared to non-transfected LNCaP cells ( Figure 12A).…”

“…Two of most commonly used prostate cancer cell lines LNCaP and PC3 are representative of prostatic adenocarcinoma and of Small Cell Neuroendocrine Carcinomas, respectively [3]. Neuroendocrine transdifferentiation of LNCaP cells can be achieved through the ectopic expression of component of the Wnt signaling pathway [4,5] or activation of STAT3 [6].…”

Activation of WNT7b autocrine eases metastasis of colorectal cancer via epithelial to mesenchymal transition and predicts poor prognosis

“…The expression of WNT7B and its co-receptors are largely restricted to specific tissues, especially the developing brain, where they contribute to blood–brain barrier formation and maintenance through activation of Wnt/β-catenin signaling [ 11 , 12 ]. Increased expression of WNT7B and subsequent Wnt pathway activation have been observed in several cancers, including prostate cancer [ 13 ], pancreatic cancer [ 14 ], and breast cancer [ 15 ]. Nevertheless, as is the case with most Wnt ligands, it remains largely unresolved how WNT7b expression is regulated as well as its underlying mechanisms in CRC.…”

Activation of WNT7b Autocrine Eases Metastasis of Colorectal Cancer via Epithelial to Mesenchymal Transition and Predicts Poor Prognosis

“…Indeed, data regarding upstream regulation of the Wnt signaling pathway is limited. A recent study from Moparthi et al found that FOXB2, an uncharacterized protein, is a potent regulator of Wnt ligand expression and TCF signaling that drives the neuroendocrine differentiation of prostate cancer cells [13]. Another study also reported that MM-1 competitively binds the wnt4 gene promotor region, thereby downregulating promoter activity of wnt4 gene expression [27].…”

“…The expression of WNT7B and its co-receptors are largely restricted to speci c tissues, especially the developing brain, where they contribute to blood-brain barrier formation and maintenance through activation of Wnt/β-catenin signaling [11,12]. Increased expression of WNT7B and subsequent Wnt pathway activation have been observed in several cancers, including prostate cancer [13], pancreatic cancer [14], and breast cancer [15]. Nevertheless, as is the case with most Wnt ligands, it remains largely unresolved how WNT7b expression is regulated as well as its underlying mechanisms in CRC.…”