EZH2 as a therapeutic target for aggressive prostate cancer

Latarani, Maryam (2023). EZH2 as a therapeutic target for aggressive prostate cancer. MPhil thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00015fc1

Abstract

Background

Prostate cancer (PCa) is a malignant neoplasia of the prostate gland. Aggressive variants of prostate cancer (AVPC) are a subtype of metastatic castration resistant PCa (mCRPC), which display reduced or absent androgen receptor (AR) -dependent signalling. AVPCs show early and extensive visceral metastases, and much worse prognosis than other PCas. Neuroendocrine prostate cancer (NEPC), often with Small Cell Carcinoma (SCC) features, is one of the AVPC subtypes. Anaplastic PCa is the other main type of AVPC. AVPCs are generally treated with platinum-based chemotherapy, but therapeutic responses are short-lived.

Epigenetic gene regulation comprises all heritable phenotypic alterations that are not caused by changes in DNA primary structure. Epigenetic alterations are attractive therapeutic targets since they are reversible and targetable by small molecule inhibitors. Some epigenetic alterations are measurable in biological fluids and could be therefore used for treatment monitoring. The main mechanisms of epigenetic regulation are histone modifications, DNA methylation, and chromatin remodelling. Histone post-translational modifications (PTMs) play a key role in the regulation of gene expression and promote tumour initiation and progression. Methylation on lysine residues has been shown to modulate gene expression. Histone methylation is catalysed by histone methyltransferases (HMTs) such as enhancer of zeste homologue 2 (EZH2). EZH2 acts in complex with suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED) to catalyse histone H3 Lys27 tri-methylation (H3K27me3) and silence target genes. H3K27me3 levels positively correlate with PCa progression and metastasis. EZH2 overexpression promotes cell viability and invasion in vivo. Three small molecule EZH2 inhibitors (Tazemetostat, GSK126, and CPI-1205) are currently in clinical trials.

Even though EZH2 has been proposed as an attractive therapeutic target in PCa, no study has explored the efficacy of combining EZH2 inhibitors with platinum-based chemotherapy in AVPC.

Materials and Methods

The expression and gene amplification of EZH2, EED and SUZ12 in clinical PCa samples were analysed by using an interactive open-source platform (cBioPortal for Cancer Genomics, http://cbioportal.org). This analysis allowed this research to correlate genetic alterations and gene expression profile of the aforementioned genes with PCa clinical features (NEPC differentiation, AR activity) and with patients’ prognosis. AVPC cells were exposed to different concentration of the three EZH2 inhibitors and their effect on cell viability were measured by cell counting; H3K27me3levels were measured via western blot from nuclear extract and via Nu.Q kit from cell supernatant. Also, the effects of combining EZH2 inhibitors with platinum agents were measured (cell viability).

Results

It was found that in PCa tissue samples, EZH2 has a higher percentage of gene amplification (i.e., gene copy number increase) compared to SUZ12 and EED. It was found that EZH2 mRNA expression had a positive correlation with NEPC features and a negative correlation with AR activity. Higher EZH2 expression also predicts a poorer prognosis in PCa patients. EZH2 inhibitors reduced intracellular H3K27me3 levels by western blot but induced modest growth inhibition in AVPC cells. GSK-126 was the most effective EZH2 inhibitors among the ones tested in this study. H3K27me3 levels were measurable in cell supernatant at all the selected timepoints and were reduced upon treatment with EZH2 inhibitors. Adding GSK-126 inhibitor to platinum agents reduced the IC50 of this chemotherapy drug.

Conclusions

The EZH2 gene is overexpressed in AVPCs. This study suggests that EZH2 inhibitors, when used in combination with platinum agents, could be an effective therapy for advanced stages of PCa. This hypothesis needs to be corroborated further in other models (e.g., patient-derived xenografts) and in clinical studies.

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