Abstract
Little is known about biological significance of ELK1, a transcriptional factor that activates downstream targets including c-fos proto-oncogene, in bladder cancer. Recent preclinical evidence also suggests the involvement of androgen receptor (AR) signaling in bladder cancer progression. In this study, we aim to investigate the functions of ELK1 in bladder cancer growth and their regulation by AR signals. Immunohistochemistry in bladder tumor specimens showed that the levels of phospho-ELK1 (p-ELK1) expression were significantly elevated in urothelial neoplasms, compared with non-neoplastic urothelium tissues, and were also correlated with AR positivity. Patients with p-ELK1-positive non-muscle-invasive and muscle-invasive tumors had significantly higher risks for tumor recurrence and progression, respectively. In AR-positive bladder cancer cell lines, dihydrotestosterone treatment increased ELK1 expression (mRNA, protein) and its nuclear translocation, ELK1 transcriptional activity, and c-fos expression, which was restored by an anti-androgen hydroxyflutamide. ELK1 silencing via short hairpin RNA (shRNA) resulted in decreases in cell viability/colony formation, and cell migration/invasion as well as an increase in apoptosis. Importantly, ELK1 appears to require activated AR to regulate bladder cancer cell proliferation, but not cell migration. Androgen also failed to significantly induce AR transactivation in ELK1-knockdown cells. In accordance with our in vitro findings, ELK1-shRNA expression considerably retarded tumor formation as well as its growth in xenograft-bearing male mice. Our results suggest that ELK1 plays an important role in bladder tumorigenesis and cancer progression, which is further induced by AR activation. Accordingly, ELK1 inhibition, together with AR inactivation, has the potential of being a therapeutic approach for bladder cancer.
Highlights
Increasing preclinical evidence suggests a critical role of steroid hormone receptor signals in the development and progression of urothelial carcinoma [1]
We aimed to identify downstream targets of androgenmediated androgen receptor (AR) signaling in bladder cancer cells
In AR knockdown cells, DHT still significantly induced ROR expression (3.3-fold), whereas it only marginally increased ELK1 expression (1.2-fold). These results suggested that androgens could up-regulate ELK1 expression through the AR pathway in bladder cancer cells
Summary
Increasing preclinical evidence suggests a critical role of steroid hormone receptor signals in the development and progression of urothelial carcinoma [1]. We and others have demonstrated the data indicating the promotion of bladder cancer growth by androgen-mediated androgen receptor (AR) activation [2,3,4,5,6,7,8,9,10,11]. Androgens have been shown to modulate the expression or activity of some molecules related to cell proliferation and/or tumor www.impactjournals.com/oncotarget growth, such as β-catenin, CD24, epidermal growth factor receptor, and extracellular signal-regulated kinases (ERK), via the AR pathway. These available data support that targeting androgens or AR provides effective therapeutic approaches for advanced bladder cancer. The involvement of ELK1 signals in cancer development, possibly via the regulation of inflammatory responses, has been documented [18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
