Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling.

Abstract

PURPOSE:

Flightless I (FLII), member of the gelsolin superfamily of actin-remodeling proteins, functions as a transcriptional coregulator. We aim to evaluate a tumor-suppressive function of FLII in regulating androgen receptor (AR) in prostate cancer progression.

EXPERIMENTAL DESIGN:

We examined FLII protein and mRNA expression in clinical prostate cancer specimens by immunohistochemistry. Kaplan-Meier analysis was conducted to evaluate the difference in disease-overall survival associated with the expression levels of FLII and AR. Prostate cancer cells stably expressing FLII or shRNA knockdown were used for functional analyses. Immunoprecipitation, Luciferase reporter, and immunofluorescence staining assays were performed to examine the functional interaction between FLII and AR.

RESULTS:

Our analysis of the expression levels of FLII in a clinical gene expression array dataset showed that the expression of FLII was positively correlated with the overall survival of prostate cancer patients exhibiting high levels of AR expression. Examination of protein and mRNA levels of FLII showed a significant decrease of FLII expression in human prostate cancers. AR and FLII formed a complex in a ligand-dependent manner through the ligand-binding domain (LBD) of AR. Subsequently, we observed a competitive binding to AR between FLII and the ligand. FLII inhibited AR transactivation and decreased AR nuclear localization. Furthermore, FLII contributed to castration-sensitive and castration-resistant prostate cancer cell growth through AR-dependent signaling, and reintroduction of FLII in prostate cancer cells sensitized the cells to bicalutamide and enzalutamide treatment.

CONCLUSIONS:

FLII plays a tumor-suppressive role and serves as a crucial determinant of resistance of prostate cancer to endocrine therapies.

• Authors: Tao Wang, Wen Song, Yuan Chen, Ruibao Chen, Zhuo Liu, Licheng Wu, Mingchao Li, Jun Yang, Liang Wang, Jihong Liu, Zhangqun Ye, Chenguang Wang, Ke Chen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 6 Pg. 1531-44 (Mar 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26527749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• FLII protein, human
• Microfilament Proteins
• Receptors, Androgen
• Receptors, Cytoplasmic and Nuclear
• Trans-Activators

Topics

• Cell Line, Tumor
• Disease Progression
• Gene Expression
• Gene Expression Profiling
• Humans
• Immunohistochemistry
• Male
• Microfilament Proteins (genetics, metabolism)
• Prognosis
• Prostatic Neoplasms (genetics, metabolism, mortality, pathology)
• Prostatic Neoplasms, Castration-Resistant (genetics, metabolism, pathology)
• Protein Binding
• Protein Interaction Domains and Motifs
• Protein Transport
• Receptors, Androgen (chemistry, genetics, metabolism)
• Receptors, Cytoplasmic and Nuclear (genetics, metabolism)
• Signal Transduction
• Trans-Activators