ELK1 is up-regulated by androgen in bladder cancer cells and promotes tumor progression

Takashi Kawahara, Hasanain Khaleel Shareef, Ali Kadhim Aljarah, Hiroki Ide, Yi Li, Eiji Kashiwagi, George J. Netto, Yichun Zheng, Hiroshi Miyamoto

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)29860-29876
Number of pages17
JournalOncotarget
Volume6
Issue number30
DOIs
StatePublished - Jan 1 2015

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Keywords

  • Androgen
  • Bladder cancer
  • ELK1
  • Immunohistochemistry
  • Tumor progression

ASJC Scopus subject areas

  • Oncology

Cite this

Kawahara, T., Shareef, H. K., Aljarah, A. K., Ide, H., Li, Y., Kashiwagi, E., Netto, G. J., Zheng, Y., & Miyamoto, H. (2015). ELK1 is up-regulated by androgen in bladder cancer cells and promotes tumor progression. Oncotarget, 6(30), 29860-29876. https://doi.org/10.18632/oncotarget.5007