You’re challenged by many drivers of disease progression1-4
The androgen receptor (AR) pathway is an established driver of progression in aPC1-3
EZH2 is under investigation as another driver of progression5
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The potential impact of EZH2 in cancer
EZH2 is implicated in the initiation and proliferation of cancer cells.6-8 Elevated EZH2 activity has been shown in multiple solid and hematological malignancies.6
EZH2 is a subunit of PRC2, a protein complex that plays a role in transcriptional silencing.5,8 EZH2 mediates epigenetic gene silencing through histone methylation.5,8
Epigenetics is the alteration of gene expression not involving changes to the DNA itself.4 A hallmark of cancer cells, epigenetic dysregulation may drive disease progression.6
Oncogenes like EZH2 sometimes cause epigenetic dysregulation, which may drive tumor proliferation and disease progression.4-6 Elevated EZH2 has been shown to correlate with certain types of cancer growth.6
PRC2=polycomb repressive complex 2.
EZH2 is the catalytic subunit of the PRC2 gene-silencing complex
PRC2 is an epigenetic protein complex that mediates gene silencing via EZH2.5,8
In preclinical studies, dysregulated PRC2 has been implicated in various tumor types.9-11
EZH2 functions as the primary enzymatic subunit of the PRC2 complex and is responsible for histone methylation, which silences tumor suppressor genes.4,5,7
EZH2 activity has been linked to the development and progression of cancer cells.6,8
EZH2 is an oncogene that may impact aPC by5:
- Silencing tumor suppressor genes
- Stimulating the AR pathway
- Impacting prostate cancer progression
EZH2 may be a driver of disease progression in aPC8
The AR pathway has been a major focus of attention in advanced prostate cancer, but preclinical studies suggest that EZH2 activity may also lead to oncogenesis and the proliferation of cancer cells. It is thought to exert oncogenic effects through multiple mechanisms.
EZH2 can control cellular development through transcriptional repression by methylating histones, which is thought to lead to epigenetic silencing of tumor suppression genes. Preclinical studies have also shown that EZH2 functions as a co-activator of transcription factors, directly interacting with ARs to promote the expression of AR target genes.
In a clinicopathological study, EZH2 activity was associated with12:
- High Gleason grade
- Advanced pathological tumor stage
- Elevated preoperative PSA level
- Early biochemical recurrence
- Increased prostate cancer cell proliferation
In a separate analysis of transcriptional profiles from a panel comparing prostate cancer and normal prostate tissue (n=498):
92% of metastatic tissue samples had increased EZH2 activity.13,14
PSA=prostate-specific antigen.
In preclinical studies
EZH2 has been shown to silence tumor suppressor genes5,8
- EZH2 is an epigenetic regulator that is thought to silence tumor suppressor genes.5
- Silencing tumor suppressor genes may lead to proliferation of prostate cancer and disease progression.5,8
Unmodified histones keep chromatin in an open or “on” state.
EZH2 methylates histones, resulting in chromatin compaction, which silences tumor suppressor genes.
When EZH2 cooperates with the AR pathway, AR activity may become increased5,7,8
Increased AR activity may contribute to prostate cancer cell proliferation and disease progression.
EZH2 is thought to activate the AR pathway.
Increased AR signaling can result in increased tumor cell proliferation.
Watch how EZH2 may impact disease progression in aPC
Investigating new potential drivers in aPC
- By silencing tumor suppressor genes and increasing AR signaling in cancer cells, EZH2 may drive progression in aPC.8
- EZH2 may play a role in aPC and is under investigation as a potential driver of disease progression.8,15
- Through the power of science, discovery, and collaboration, we are investigating EZH2-mediated effects on the progression of aPC.
Clinical trials studying the potential of EZH2 in aPC are ongoing
References: 1. Bai Y, et al. J Biol Chem. 2019;294(25):9911-9923. 2. Chatterjee SS, et al. Nat Commun. 2024;15(1):9755. 3. Shankar E, et al. Toxicol Appl Pharmacol. 2020;404:115200. 4. Ragavi R, et al. Urol Oncol. 2023;41(8):340-353. 5. Kim J, et al. Cell Rep. 2018;25(10):2808-2820.e4. 6. Kung PP, et al. J Med Chem. 2018;61(3):650-665. 7. Ku SY, et al. Science. 2017;355(6320):78-83. 8. Park SH, et al. Oncogene. 2021;40(39):5788-5798. 9. El Hassan MA, et al. PLoS ONE. 2015;10(6):e0126466. 10. Erokhin M, et al. Cancers (Basel). 2021;13(13):3155. 11. Crea F, et al. Mol Cancer. 2011;10:40. 12. Melling N, et al. Carcinogenesis. 2015;36(11):1333-1340. 13. Schade AE. PLoS Biol. 2023;21(4):e3002038. 14. Broad Institute TCGA Genome Data Analysis Center. Broad Institute of MIT and Harvard; 2016. 15. Berger A, et al. J Clin Invest. 2019;129(9):3924-3940.