Fascin-1 expression is associated with neuroendocrine prostate cancer and directly suppressed by androgen receptor

Abstract

Endocrine cancer

Càncer endocrí

Cáncer endocrino

Background Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular mechanisms associated with NEPC development and invasiveness are still poorly understood. Here we investigated the expression and functional significance of Fascin-1 (FSCN1), a pro-metastasis actin-bundling protein associated with poor prognosis of several cancers, in neuroendocrine differentiation of prostate cancer. Methods Differential expression analyses using Genome Expression Omnibus (GEO) database, clinical samples and cell lines were performed. Androgen or antagonist’s cellular treatments and knockdown experiments were used to detect changes in cell morphology, molecular markers, migration properties and in vivo tumour growth. Chromatin immunoprecipitation-sequencing (ChIP-Seq) data and ChIP assays were analysed to decipher androgen receptor (AR) binding. Results We demonstrated that FSCN1 is upregulated during neuroendocrine differentiation of prostate cancer in vitro, leading to phenotypic changes and NEPC marker expression. In human prostate cancer samples, FSCN1 expression is restricted to NEPC tumours. We showed that the androgen-activated AR downregulates FSCN1 expression and works as a transcriptional repressor to directly suppress FSCN1 expression. AR antagonists alleviate this repression. In addition, FSCN1 silencing further impairs in vivo tumour growth. Conclusion Collectively, our findings identify FSCN1 as an AR-repressed gene. Particularly, it is involved in NEPC aggressiveness. Our results provide the rationale for the future clinical development of FSCN1 inhibitors in NEPC patients.

This work was funded by CNRS (Centre national de recherche scientifique), INSERM (Institut national de la santé et de la recherche médicale), Université de Lille, Institut Pasteur de Lille, and supported by grants from Ligue nationale contre le Cancer (Comité de l’Aisne), Institut national du cancer (INCa_4419), ARTP (Association de Recherche sur les tumeurs de prostate). This work is supported by a grant from Contrat de Plan Etat-Région CPER Cancer 2015–2020. Work performed at the laboratory of TVT was supported by Spanish Plan Estatal de I + D + I (PID2019-108008RJ-I00), AECC (INVES20036TIAN), Ramón y Cajal investigator programme (RYC2020-029098-I), and FERO Foundation. CD was supported by Institut Pasteur de Lille, Conseil Régional des Hauts-de-France and Fondation pour la Recherche Médicale (FRM).