Hexim-1 modulates androgen receptor and the TGF-β signaling during the progression of prostate cancer

• Published in: The Prostate Vol. 72; no. 9; pp. 1035 - 1044
• Main Authors: Mascareno, Eduardo J., Belashov, Ivan, Siddiqui, M. A. Q., Liu, Fang, Dhar-Mascareno, Manya
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.06.2012
• Subjects: androgen receptor; Animals; Disease Progression; HEXIM1; Humans; Male; Mice; Mice, Transgenic; mouse model; Phosphorylation; prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, Androgen - metabolism; Receptors, Androgen - physiology; RNA polymerase; serine phosphorylation; Signal Transduction - physiology; SMAD phosphorylation; Smad Proteins - metabolism; Smad Proteins - physiology; TGF-β; Transcription Factors - physiology; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - physiology
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.21510

BACKGROUND Androgen and TGF‐β signaling are important components during the progression of prostate cancer. However, whether common molecular events participate in the activation of these signaling pathways are less understood. METHOD Hexim 1 expression was detected by immunohistochemistry of human tissue microarrays and TRAMP mouse models. The in vivo significance of Hexim‐1 was established by crossing the TRAMP mouse model of prostate cancer with Hexim‐1 heterozygous mice. TRAMP C2 cell line was also modified to delete one copy of Hexim‐1 gene to generate TRAMP‐C2‐Hexim‐1+/− cell lines. RESULTS In this report, we observed that Hexim‐1 protein expression is absent in normal prostate but highly expressed in adenocarcinoma of the prostate and a characteristic sub‐cellular distribution among normal, benign hyperplasia, and adenocarcinoma of the prostate. Heterozygosity of the Hexim‐1 gene in the prostate cancer mice model and the TRAMP‐C2 cell line, leads to increased Cdk9‐dependent serine phosphorylation on protein targets such as the androgen receptor (AR) and the TGF‐β‐dependent downstream transcription factors, such as the SMAD proteins. CONCLUSION Our results suggest that changes in the Hexim‐1 protein expression and cellular distribution significantly influences the AR activation and the TGF‐β signaling. Thus, Hexim‐1 is likely to play a significant role in prostate cancer progression. Prostate 72:1035–1044, 2012. © 2011 Wiley Periodicals, Inc.