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Updated: Oct 28, 2025
08:01
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
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CDKN2A Determines Mesothelioma Cell Fate to EZH2 Inhibition
Giulia Pinton1, Zhuo Wang2, Cecilia Balzano1
1Department of Pharmaceutical Sciences, University of Piemonte Orientale (UPO), Novara, Italy.
Frontiers in Oncology
|July 19, 2021
Summary
Malignant mesothelioma cells with wild-type BAP1 become sensitive to EZH2 inhibition when SIRT1 is silenced or in spheroids. CDKN2A expression predicts apoptosis response to EZH2 inhibitors, aiding treatment stratification.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Malignant pleural mesothelioma is an aggressive cancer with varied behavior.
- Molecular markers are known but underutilized for treatment allocation.
- Mesothelioma cells lacking BAP1 (BRCA1 Associated Protein) show sensitivity to EZH2 (Enhancer of Zeste Homolog 2) inhibition.
Purpose of the Study:
- To investigate the in vitro response of BAP1 wild-type mesothelioma cells to the EZH2 inhibitor EPZ-6438.
- To explore conditions sensitizing BAP1 wild-type mesothelioma cells to EZH2 inhibition.
- To determine the role of CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A) in mediating cell fate upon EZH2 inhibition.
Main Methods:
- In vitro culture of BAP1 wild-type mesothelioma cells as monolayers and multicellular spheroids.
- Silencing or inhibition of SIRT1 (Sirtuin 1).
- Treatment with EZH2 inhibitor EPZ-6438, alone or in combination with other agents (e.g., TG2 inhibitor 1-155) or genetic modifications (e.g., CDKN2A silencing).
- Analysis of H3K27me3 (histone H3 lysine 27 trimetylation) levels, gene expression (CDKN2A, HIF2α, TG2, IL-6), and cell death induction (apoptosis, growth arrest).
Main Results:
- BAP1 wild-type mesothelioma cells were sensitized to EPZ-6438 by SIRT1 silencing/inhibition or by culturing as multicellular spheroids (where SIRT1 expression was lower).
- EPZ-6438 treatment in spheroids reduced H3K27me3, upregulated CDKN2A, and caused growth arrest.
- EPZ-6438 induced HIF2α (Hypoxia Inducible Factor 2α), TG2 (Transglutaminase 2), and IL-6 (Interleukin 6) expression.
- Combined EPZ-6438 and CDKN2A silencing induced apoptosis in spheroids.
- In a CDKN2A wild-type setting, combining EPZ-6438 with a TG2 inhibitor (1-155) induced apoptosis.
Conclusions:
- SIRT1 modulation and spheroid culture sensitize BAP1 wild-type mesothelioma cells to EZH2 inhibition.
- CDKN2A expression status is a critical determinant of cell fate (growth arrest vs. apoptosis) in response to EZH2 inhibition.
- CDKN2A may serve as a predictive biomarker for stratifying mesothelioma patients for EZH2-targeted therapies.
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