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Updated: Mar 22, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
EZH2 as a mediator of treatment resistance in melanoma
Jessamy C Tiffen1, Stuart J Gallagher1, Hsin-Yi Tseng1
1Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Camperdown, NSW, Australia.
Abstract:
Direct treatments of cancer such as chemotherapy, radiotherapy and targeted therapy have been shown to depend on recruitment of the immune system for their effectiveness. Recent studies have shown that development of resistance to direct therapies such as BRAF inhibitors in melanoma is associated with suppression of immune responses. We point to emerging data that implicate activation of the polycomb repressive complex 2 (PRC2) and its catalytic component-enhancer of zeste homolog 2 (EZH2)-in progression of melanoma and suppression of immune responses. EZH2 appears to have an important role in differentiation of CD4 T cells and particularly in the function of T regulatory cells, which suppress immune responses to melanoma. We review mechanisms of EZH2 activation at the genomic level and from activation of the MAP kinase, E2F or NF-kB2 pathways. These studies are consistent with activation of EZH2 as a common mechanism for induction of immune suppression in patients failing direct therapies and suggest EZH2 inhibitors may have a role in combination with immunotherapy and targeted therapies to prevent development of immunosuppression.
Insights
Activation of EZH2 suppresses immune responses in melanoma, hindering cancer therapies. EZH2 inhibitors may restore immune function when combined with immunotherapy and targeted treatments.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Cancer therapies like chemotherapy and targeted therapy rely on immune system activation.
- Resistance to treatments, such as BRAF inhibitors for melanoma, is linked to suppressed immune responses.
Purpose of the Study:
- To explore the role of Polycomb Repressive Complex 2 (PRC2), specifically enhancer of zeste homolog 2 (EZH2), in melanoma progression and immune suppression.
- To review mechanisms of EZH2 activation and its impact on T cell differentiation and regulatory T cell function.
Main Methods:
- Review of emerging data and scientific literature on EZH2, melanoma, and immune responses.
- Analysis of genomic and pathway-specific mechanisms (MAP kinase, E2F, NF-kB2) leading to EZH2 activation.
Main Results:
- EZH2 activation is implicated in melanoma progression and immune suppression.
- EZH2 plays a critical role in CD4 T cell differentiation and the function of immunosuppressive T regulatory cells in melanoma.
Conclusions:
- EZH2 activation is a common mechanism for immune suppression in patients resistant to direct cancer therapies.
- EZH2 inhibitors show potential for combination therapy with immunotherapy and targeted treatments to overcome immunosuppression and enhance treatment efficacy.
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