Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 44; pp. 22189 - 22195
• Main Authors: Moparthi, Lavanya, Pizzolato, Giulia, Koch, Stefan
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.10.2019
• Subjects: Biological Sciences; Cell Differentiation; Cofactors; Data analysis; DEAD-box RNA Helicases - metabolism; Differentiation; Embryos; Forkhead protein; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene expression; HCT116 Cells; HEK293 Cells; Humans; LEF protein; Male; Neuroendocrine Cells - cytology; Neuroendocrine Cells - metabolism; Prostate cancer; Prostatic Neoplasms - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Regulators; Ribonucleic acid; RNA; Signal transduction; Signaling; Tumor cell lines; Wnt protein; Wnt Proteins - metabolism; Wnt Signaling Pathway; YY1 protein; YY1 Transcription Factor - metabolism; β-Catenin; FOXB2; Wnt signaling; prostate cancer; forkhead
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1906484116

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.