Abstract 1801: FOXA1, a novel regulator of neuroendocrine differentiation

Abstract Neuroendocrine prostate cancer (NEPC) is a subtype of prostate cancer that is highly aggressive and exhibits a neuroendocrine phenotype, being distinct from prostate adenocarcinoma. Cases of NEPC are predicted to increase rapidly following broader use of new-generation hormonal therapies including abiraterone and enzalutamide. Although androgen deprivation and cytokine induction have been previously suggested to induce neuroendocrine differentiation of prostate cancer, little is known regarding the underlying molecular mechanisms. FOXA1 is a forkhead box family transcription factor that has been shown to act as a pioneer factor for androgen receptor (AR), thereby defining the prostatic transcriptional program. We have recently shown that FOXA1 plays an important role in suppressing epithelial-to-mesenchymal transdifferentiation, but is often downregulated in castration-resistant prostate cancer (CRPC). Along this line, in the present study, we showed that FOXA1 loss, achieved by shRNA-mediated knockdown, led to cell morphology changes typical of neuroendocrine differentiation, accompanied by a strong increase of NEPC marker enolase2 (ENO2), while ectopic FOXA1 overexpression reverses these alterations. This was further linked to ERK phosphorylation, which has been previously reported to be up-regulated following neuroendocrine differentiation. Moreover, to understand the mechanism underlying FOXA1 regulation of neuroendocrine differentiation, we performed bioinformatics analysis and nominated interleukin 8 (IL8) as a direct target of FOXA1 and its up-regulation is critical in mediating neuroendocrine differentiation of FOXA1-depleted cells. Finally, we validated a negative correlation between FOXA1 and neuroendocrine differentiation in primary prostate cancer specimens through analysis of publically available RNA-seq data as well as direct IHC staining of various NEPC markers. In summary, we report a new role of FOXA1 as a critical inhibitor of neuroendocrine differentiation and the importance of balanced FOXA1 expressing in the maintenance of the epithelial phenotype of prostate cancer. Citation Format: Jung Kim, Hongjian Jin, Jonathan Zhao, Vamsi Parimi, Ximing Yang, Jindan Yu. FOXA1, a novel regulator of neuroendocrine differentiation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1801.