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.
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.
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.
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.
British journal of cancer. 2023 Oct 24 [Epub ahead of print]
Anthony Turpin, Carine Delliaux, Pauline Parent, Hortense Chevalier, Carmen Escudero-Iriarte, Franck Bonardi, Nathalie Vanpouille, Anne Flourens, Jessica Querol, Aurélien Carnot, Xavier Leroy, Nicolás Herranz, Tristan Lanel, Arnauld Villers, Jonathan Olivier, Hélène Touzet, Yvan de Launoit, Tian V Tian, Martine Duterque-Coquillaud
University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France., Vall d'Hebron Institute of Oncology (VHIO), 08035, Barcelona, Spain., University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000, Lille, France., Department of Medical Oncology, Centre Oscar Lambret, 3, rue Frederic Combemale, 59000, Lille, France., University Lille, CNRS, Centrale Lille, UMR 9189 CRIStAL, F-59000, Lille, France., University Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France. .