Dual Effect of EZH2 Gene Editing with CRISPR/Cas9 in Lung Cancer

TL;DR

This study shows that editing the EZH2 gene in lung cancer has both tumor-suppressing and tumor-promoting effects depending on the context, highlighting challenges in targeting this gene for treatment.

Contribution

The study reveals a dual and context-dependent role of EZH2 in lung cancer, emphasizing compensatory mechanisms when targeting this epigenetic regulator.

Findings

EZH2 inhibition in vitro reduces cell proliferation and promotes differentiation-related gene expression.

EZH2 gene-edited cells form larger tumors in mice, accompanied by increased expression of other PcG genes.

Compensatory interactions between PRC2 and PRC1 complexes suggest challenges in targeting EZH2 alone for therapy.

Abstract

Searching for new molecular targets for lung cancer is essential to understand aggressiveness and early metastatic spread and provide new treatment alternatives. This study indicates a dual and cell context-dependent role for EZH2 activation and points out the challenges of targeting this epigenetic regulator in lung cancer. Our findings demonstrate that EZH2 inhibition induces tumor suppressor effects in vitro, promoting cell differentiation, but can trigger compensatory epigenetic mechanisms that promote tumor progression in vivo. This study highlights the plasticity of the networks regulated by Polycomb group (PcG) genes, raising important considerations for the use of epigenetic therapies in lung cancer, including EZH2 inhibitors or even EZH2 gene editing, either alone or in combination with the inhibition of other PcG genes.

Lung adenocarcinoma is the most common form of lung cancer with a 5-year survival rate of 15%, largely due to asymptomatic metastasis and late diagnosis. Overexpression of Polycomb group (PcG) proteins, particularly EZH2, the catalytic component of Polycomb Repressive Complex 2 (PRC2), has been associated with the pathogenesis of lung cancer, frequently showing correlation with cancer progression and poor prognosis. In this study, EZH2 levels were modulated by CRISPR/Cas9 gene editing and PRC2 activity was inhibited with EZH2 inhibitor EPZ6438 or EED inhibitor MAK683. EZH2 gene editing reduced cell proliferation, migration, invasion, and colony formation and reduced NFκ-B signaling activation, indicating an antitumoral effect in vitro. Moreover, EZH2 inhibition also increased the expression of differentiation-related genes, such as GATA5, FOXA2, and lung surfactants, indicating a pro-differentiation effect. However, EZH2-edited cells injected into an immunocompromised mouse model generated larger tumors compared to unedited cells. This was accompanied by increased expression of other PcG genes, including EZH1, CBX2, RING1, EED, and SUZ12, suggesting a compensatory interaction between PRC2 and PRC1 complexes. These findings provide significant clinical relevance, both in elucidating the mechanisms of novel molecular targets and in guiding treatment strategies for lung cancer when using epigenetic inhibitors.

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