Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer
Menée à l'aide de lignées cellulaires de cancer de la prostate, cette étude met en évidence un mécanisme par lequel le facteur de transcription FOXB2, un activateur de la voie de signalisation des protéines Wnt, favorise la différenciation neuroendocrine des cellules cancéreuses
Aberrant activation of the homeostatic Wnt signaling pathway is a hallmark of various types of cancer. In many cases, it is unclear how elevated Wnt levels are maintained in the absence of activating pathway mutations. Here we find that the uncharacterized transcription factor FOXB2, whose expression is usually restricted to the developing brain, is induced in aggressive prostate cancer. FOXB2 strongly activates Wnt signaling via the induction of multiple pathway agonists, particularly the neurogenic ligand WNT7B. Accordingly, our analyses suggest that FOXB2 imposes a neuronal differentiation program on prostate cancer cells, which is associated with treatment failure and poor prognosis. Thus, our work identifies FOXB2 as a tissue-specific Wnt activator that may play a role in prostate cancer progression.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.