FOXA1 inhibits prostate cancer neuroendocrine differentiation.

Abstract:

:Neuroendocrine prostate cancer (NEPC) has increasingly become a clinical challenge. The mechanisms by which neuroendocrine (NE) cells arises from prostate adenocarcinoma cells are poorly understood. FOXA1 is a transcription factor of the forkhead family that is required for prostate epithelial differentiation. In this study, we demonstrated that FOXA1 loss drives NE differentiation, demarcated by phenotypical changes and NEPC marker expressions. Mechanistically, this is mediated by FOXA1 binding to the promoter of interleukin 8 (IL-8), a chemokine previously shown elevated in NEPC, to directly inhibit its expression. Further, IL-8 upregulation activates the MAPK/ERK pathway, leading to ERK phosphorylation and enolase 2 (ENO2) expression. IL-8 knockdown or ERK inhibition, on the other hand, abolished FOXA1 loss-induced NE differentiation. Analysis of xenograft mouse models confirmed FOXA1 loss in NEPC tumors relative to its adenocarcinoma counterparts. Importantly, FOXA1 is downregulated in human NEPC tumors compared to primary and castration-resistant prostate cancers, and its expression is negatively correlated with that of ENO2. These findings indicate that FOXA1 transcriptionally suppresses IL-8, the expression of which would otherwise stimulate the MAPK/ERK pathway to promote NE differentiation of prostate cancer cells. Our data strongly suggest that FOXA1 loss may play a significant role in enabling prostate cancer progression to NEPC, whereas IL-8 and MAPK/ERK pathways may be promising targets for therapeutic intervention.

journal_name

Oncogene

journal_title

Oncogene

authors

Kim J,Jin H,Zhao JC,Yang YA,Li Y,Yang X,Dong X,Yu J

doi

10.1038/onc.2017.50

subject

Has Abstract

pub_date

2017-07-13 00:00:00

pages

4072-4080

issue

28

eissn

0950-9232

issn

1476-5594

pii

onc201750

journal_volume

36

pub_type

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