Related Experiment Video
Updated: Dec 1, 2025
Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
Published on: May 30, 2025
Targeting the polycomb repressive complex-2 related proteins with novel combinational strategies for nasopharyngeal
Junyu Zhu1, Lili Li1, Joanna Tong2
1State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital Hong Kong, China.
Abstract:
Aberrant epigenetic regulation is critically involved in the pathogenesis of nasopharyngeal carcinoma (NPC), where abnormal histone methylation can be found in polycomb repressive complex-2 (PRC2) related cancer gene loci. This study investigated some novel combinational strategies against NPC in vitro using PRC2-targeting agents as a backbone. PRC2 subunit proteins were overexpressed in over 70% of NPC tumors and enhancer of zeste homolog-2 (EZH2) expression correlated with more advanced T-stage. Basal expression of EZH2 and embryonic ectoderm development (EED) was higher in Epstein-Bar virus (EBV)+ NPC cells than EBV- cells. Treatment with an EED inhibitor (EED226) led to reduced levels of H3K27me3 with minimal inhibitory effect on NPC cell growth. The combination of an EZH2 inhibitor (EPZ-6438) and trichostatin-A (TSA) yielded the highest synergy score (12.64) in NPC cells in vitro than combinations using EED226 and agents like chemotherapy and azacitadine. Global gene expression analysis showed that EED226 predominantly affects the expression of major histocompatibility complex (MHC) class I genes and cell cycle-related genes in NPC cells. Furthermore, treatment with EED226 resulted in increased MHC-I proteins in vitro. Based on the prediction of an artificial neural network, a synergistic inhibitory effect on growth was found by combining EED226 with cyclin dependent kinase (CDK) 4/6 inhibitor (LEE011) in NPC cells. In summary, this study found that PRC2-targeting agents could exert synergistic effect on growth inhibition when combined with TSA or LEE011 in NPC cells. Since MHC-I genes alterations are found in a third of NPC tumors, the effect of EED226 on MHC-I genes expression on response to immunotherapy in NPC warrants further investigations.
Insights
Novel combinations targeting Polycomb Repressive Complex 2 (PRC2) show promise against nasopharyngeal carcinoma (NPC). Combining EZH2 or EED inhibitors with other agents like TSA or LEE011 demonstrated synergistic NPC cell growth inhibition.
Area of Science:
- Oncology
- Epigenetics
- Cancer Biology
Background:
- Aberrant epigenetic regulation, specifically histone methylation by Polycomb Repressive Complex 2 (PRC2), is implicated in nasopharyngeal carcinoma (NPC) pathogenesis.
- PRC2 subunit proteins, including enhancer of zeste homolog-2 (EZH2) and embryonic ectoderm development (EED), are overexpressed in NPC tumors, correlating with advanced disease stages.
- Epstein-Bar virus (EBV) positivity in NPC cells is associated with higher basal expression of EZH2 and EED.
Purpose of the Study:
- To investigate novel combinational therapeutic strategies against NPC using PRC2-targeting agents.
- To evaluate the efficacy of combining EED inhibitors (EED226) and EZH2 inhibitors (EPZ-6438) with other agents in NPC cell lines.
- To explore the impact of PRC2 inhibition on gene expression, particularly major histocompatibility complex (MHC) class I genes, and its potential synergy with immunotherapy.
Main Methods:
- In vitro assessment of NPC cell growth inhibition using PRC2 inhibitors (EED226, EPZ-6438) alone and in combination with trichostatin-A (TSA), chemotherapy, azacitadine, and cyclin-dependent kinase (CDK) 4/6 inhibitor (LEE011).
- Analysis of H3K27me3 levels and global gene expression changes following EED226 treatment.
- Prediction of synergistic drug combinations using artificial neural networks.
Main Results:
- Treatment with EED226 reduced H3K27me3 levels but had minimal impact on NPC cell growth alone.
- The combination of EZH2 inhibitor EPZ-6438 and TSA showed the highest synergy score in NPC cells.
- EED226 predominantly affected the expression of MHC class I and cell cycle-related genes, increasing MHC-I protein levels.
- Artificial neural network prediction identified a synergistic growth inhibitory effect for the combination of EED226 and LEE011.
Conclusions:
- PRC2-targeting agents can achieve synergistic NPC growth inhibition when combined with TSA or LEE011.
- EED226's effect on MHC-I gene expression suggests potential implications for immunotherapy response in NPC, warranting further investigation.
- Combinatorial epigenetic therapy targeting PRC2 presents a promising avenue for NPC treatment.
More Related Videos
10:26Toxicological Assays for Testing Effects of an Epigenetic Drug on Development, Fecundity and Survivorship of Malaria Mosquitoes
Published on: January 16, 2015
14:20Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...