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Application of MassSQUIRM for Quantitative Measurements of Lysine Demethylase Activity
Published on: March 11, 2012
LSD1 activates a lethal prostate cancer gene network independently of its demethylase function
Archana Sehrawat1, Lina Gao1, Yuliang Wang2,3
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239.
Abstract:
Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.
Insights
Lysine-specific demethylase 1 (LSD1) promotes lethal prostate cancer survival, even when resistant to castration. Inhibiting LSD1 shows promise for treating advanced prostate cancer by blocking key survival pathways.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Advanced prostate cancer treatment relies on medical castration targeting the androgen receptor (AR).
- Tumor progression and resistance to castration are common, necessitating novel therapeutic strategies.
- Lysine-specific demethylase 1 (LSD1) regulates gene expression and is implicated in cancer progression.
Purpose of the Study:
- To investigate the role of LSD1 in prostate cancer survival, particularly in castration-resistant cases.
- To explore the mechanisms by which LSD1 promotes cancer cell survival, independent of AR signaling.
- To evaluate the therapeutic potential of LSD1 inhibition in lethal prostate cancer.
Main Methods:
- Investigated LSD1's function in prostate cancer cell lines, including castration-resistant models.
- Assessed LSD1's interaction with ZNF217 and its role in activating gene networks.
- Utilized a small-molecule LSD1 inhibitor (SP-2509) to assess its effects on cell viability and function.
Main Results:
- LSD1 promotes the survival of both hormone-sensitive and castration-resistant prostate cancer cells.
- LSD1's pro-survival role is independent of its demethylase activity and AR signaling.
- LSD1 collaborates with ZNF217 to activate a gene network associated with lethal prostate cancer.
- The LSD1 inhibitor SP-2509 suppressed castration-resistant prostate cancer cell viability by blocking demethylase-independent functions.
Conclusions:
- LSD1 is a critical driver of prostate cancer cell survival, irrespective of AR status.
- Targeting LSD1, particularly its demethylase-independent functions, represents a promising therapeutic strategy for advanced and castration-resistant prostate cancer.
- LSD1 inhibition offers a novel approach to overcome treatment resistance in lethal prostate cancer.
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