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Updated: Jan 11, 2026
Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer
Published on: November 2, 2013
EZH2 Suppression Diversifies Prostate Cancer Lineage Variant Evolution and Lacks Efficacy in Inhibiting Disease
Justine J Jacobi1,2, Kristine M Wadosky3, Neha Jaiswal3
1Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Abstract:
Advanced prostate cancer remains a leading cause of cancer-related death among men due to disease progression in nearly all patients on standard-of-care therapy targeting the androgen receptor. An important mechanism driving therapeutic resistance is lineage plasticity, which enables prostate cancer cells to reprogram into lineage variants no longer dependent on androgen receptor signaling. As inhibitors of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) are being evaluated clinically for the treatment of advanced prostate cancer, we investigated in this study how EZH2 affects prostate cancer lineage plasticity. Data from genetically engineered mice and human clinical samples demonstrated that genetic or pharmacologic suppression of EZH2 altered chromatin to expand active transcription factor programs. These changes in gene expression during prostate cancer progression increased the diversity of prostate cancer lineage variants that arose. EZH2 suppression did not inhibit disease progression nor therapeutic resistance in this context. These findings advance the current understanding of prostate cancer lineage plasticity and suggest that EZH2 inhibitors may be less effective in treating prostate cancer prone to lineage plasticity.
Significance:
EZH2 suppression diversifies prostate cancer lineage plasticity, which has implications for EZH2-targeted therapies that are being evaluated for prostate cancer treatment. See related commentary by Thienger et al., p. 827.
Insights
In advanced prostate cancer (PrCa), suppressing EZH2 increases cancer cell diversity and lineage plasticity, potentially limiting the effectiveness of EZH2 inhibitors for treating this disease.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Advanced prostate cancer (PrCa) is a major cause of cancer death in men.
- Therapeutic resistance in PrCa is often driven by lineage plasticity, where cancer cells adapt to evade androgen receptor signaling.
- Histone methyltransferase EZH2 inhibitors are under clinical evaluation for advanced PrCa.
Purpose of the Study:
- To investigate the role of EZH2 in prostate cancer (PrCa) lineage plasticity.
- To determine the impact of EZH2 suppression on PrCa progression and therapeutic resistance.
Main Methods:
- Utilized genetically engineered mouse models of PrCa.
- Analyzed human clinical samples.
- Assessed the effects of genetic and pharmacological EZH2 suppression on chromatin and gene expression.
- Evaluated changes in PrCa lineage variant diversity and disease progression.
Main Results:
- Genetic or pharmacological suppression of EZH2 altered chromatin structure.
- EZH2 suppression led to expanded active transcription factor programs.
- Increased gene expression diversity resulted in a greater variety of PrCa lineage variants.
- EZH2 suppression did not inhibit disease progression or therapeutic resistance in this model.
Conclusions:
- EZH2 plays a role in regulating PrCa lineage plasticity.
- Suppression of EZH2 increases the diversity of PrCa lineage variants.
- EZH2 inhibitors may have limited efficacy in treating advanced PrCa prone to lineage plasticity.
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