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The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer
Vasundhra Kashyap1, Shafqat Ahmad, Emeli M Nilsson
1Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
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.
Insights
Lysine specific demethylase-1 (LSD1) overexpression correlates with prostate cancer recurrence and increased VEGF-A. Inhibiting LSD1 reduces cancer cell proliferation, suggesting it as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Recurrent prostate cancer presents a significant clinical challenge.
- Lysine specific demethylase-1 (LSD1/KDM1A) is a key regulator of histone methylation, implicated in various cancers.
- LSD1 functions as a transcriptional co-regulator and influences DNA methylation and p53 activity.
Purpose of the Study:
- To investigate the expression of LSD1 and JMJD2A in human prostate cancer specimens.
- To correlate LSD1 and JMJD2A expression with prostate cancer progression markers like VEGF-A and cyclin A1.
- To explore the therapeutic potential of targeting LSD1 in prostate cancer.
Main Methods:
- Expression analysis of LSD1 and JMJD2A in prostate cancer tissues.
- Correlation studies between LSD1/JMJD2A expression and VEGF-A/cyclin A1 levels.
- siRNA-mediated functional depletion of LSD1 in prostate cancer cells.
- Pharmacological inhibition of LSD1 in androgen-dependent and independent cell lines.
Main Results:
- Elevated LSD1 expression, but not JMJD2A, correlates with prostate cancer recurrence and increased VEGF-A.
- Functional depletion of LSD1 reduces VEGF-A expression and blocks androgen-induced expression of VEGF-A, PSA, and Tmprss2.
- Pharmacological inhibition of LSD1 inhibits proliferation in both androgen-dependent and independent prostate cancer cell lines.
- A direct mechanistic link between LSD1 overexpression and pro-angiogenic pathway activation was established.
Conclusions:
- LSD1 overexpression is linked to prostate cancer progression and angiogenesis.
- Targeting LSD1 offers a promising therapeutic strategy for both hormone-dependent and independent prostate cancer.
- LSD1 inhibition demonstrates efficacy in reducing prostate cancer cell proliferation.
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