The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer.

Abstract

Recurrent prostate cancer remains a major clinical challenge. The lysine specific demethylase-1 (LSD1/KDM1A), together with the JmjC domain-containing JMJD2A and JMJD2C proteins, have emerged as critical regulators of histone lysine methylation. The LSD1-JMJD2 complex functions as a transcriptional co-regulator of hormone activated androgen and estrogen receptors at specific gene promoters. LSD1 also regulates DNA methylation and p53 function. LSD1 is overexpressed in numerous cancers including prostate cancer through an unknown mechanism. We investigated expression of the LSD1 and JMJD2A in malignant human prostate specimens. We correlated LSD1 and JMJD2A expression with known mediators of prostate cancer progression: VEGF-A and cyclin A1. We show that elevated expression of LSD1, but not JMJD2A, correlates with prostate cancer recurrence and with increased VEGF-A expression. We show that functional depletion of LSD1 expression using siRNA in prostate cancer cells decreases VEGF-A and blocks androgen induced VEGF-A, PSA and Tmprss2 expression. We demonstrate that pharmacological inhibition of LSD1 reduces proliferation of both androgen dependent (LnCaP) and independent cell lines (LnCaP: C42, PC3). We show a direct mechanistic link between LSD1 over-expression and increased activity of pro-angiogenic pathways. New therapies targeting LSD1 activity should be useful in the treatment of hormone dependent and independent prostate cancer.

• Authors: Vasundhra Kashyap, Shafqat Ahmad, Emeli M Nilsson, Leszek Helczynski, Sinéad Kenna, Jenny Liao Persson, Lorraine J Gudas, Nigel P Mongan
• Journal: Molecular oncology (Mol Oncol) Vol. 7 Issue 3 Pg. 555-66 (Jun 2013) ISSN: 1878-0261 [Electronic] United States
• PMID: 23384557 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Androgens
• Cyclin A1
• Vascular Endothelial Growth Factor A
• Histone Demethylases
• KDM1A protein, human

Topics

• Androgens (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cyclin A1 (genetics)
• Gene Expression Regulation, Neoplastic
• Histone Demethylases (analysis, genetics, metabolism)
• Humans
• Male
• Middle Aged
• Prostate (enzymology, metabolism, pathology)
• Prostatic Neoplasms (enzymology, genetics, pathology)
• RNA Interference
• Transcriptional Activation
• Vascular Endothelial Growth Factor A (genetics, metabolism)