Abstract
The nonreceptor tyrosine kinase Etk/BMX was originally identified from the human prostate xenograft CWR22. Here, we report that Etk is up-regulated in human prostate tumor specimens surveyed. Knocking down Etk expression by a specific small interfering RNA (siRNA) in prostate cancer cells attenuates cell proliferation, suggesting an essential role of Etk for prostate cancer cell survival and growth. Targeted expression of Etk in mouse prostate epithelium results in pathologic changes resembling human prostatic intraepithelial neoplasia, indicating that up-regulation of Etk may contribute to prostate cancer development. A marked increase of luminal epithelial cell proliferation was observed in the Etk transgenic prostate, which may be attributed in part to the elevated activity of Akt and signal transducers and activators of transcription 3 (STAT3). More interestingly, the expression level of acetyltransferase cyclic AMP-responsive element binding protein-binding protein (CBP) is also increased in the Etk transgenic prostate as well as in a prostate cancer cell line overexpressing Etk, concomitant with elevated histone 3 acetylation at lysine 18 (H3K18Ac). Down-modulation of Etk expression by a specific siRNA leads to a decrease of H3 acetylation in prostate cancer cell lines. Our data suggest that Etk may also modulate chromatin remodeling by regulating the activity of acetyltransferases, such as CBP. Given that Etk may exert its effects in prostate through modulation of multiple signaling pathways altered in human prostate cancer, the Etk transgenic mouse model may be a useful tool for studying the functions of Etk and identification of new molecular markers and drug targets relevant to human diseases.
Highlights
Prostate cancer is the most commonly diagnosed cancer among men in the Western world
To examine the expression of Etk in human prostate tumor tissues, immunohistochemical analysis was done on four tissue arrays containing a total of 230 prostate specimens, including 59 benign and 171 prostate tumor samples
To further confirm prostate-specific Etk expression in prostate epithelial cells, the prostate from wild-type (WT) mice and Etk transgenic mice at the age of 12 weeks were carefully dissected, and targeted Etk expression was examined by immunohistochemistry and Western blot analysis
Summary
Prostate cancer is the most commonly diagnosed cancer among men in the Western world. Despite intensive investigations in the past decades, the molecular basis underlying prostate cancer development and progression is not yet completely understood. Numerous genetic and epigenetic alterations, including loss of tumor suppressors (e.g., Pten, Nkx3.1, p53, and Rb) and amplification of oncogenes (e.g., Myc, FGF8b), have been reported to associate with prostate cancer [3, 4]. A number of experimental approaches have been used to assess the contribution of a given genetic/epigenetic alteration to prostate cancer development and/or progression. A series of genetically modified animal models for prostate cancer have been established [5, 6], other animal models that recapitulate human disease process are still in demand to fully understand the molecular basis of prostate cancer
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