Ezh2Y641F mutations co-operate with Stat3 to regulate MHC class I antigen processing and alter the tumor immune response in melanoma

Zimmerman, Sarah M.; Nixon, Samantha J.; Chen, Pei-Yu; Raj, Leela; Smith, Sofia R.; Paolini, Rachel L.; Lin, Phyo Nay; Souroullas, George P.

doi:10.1038/s41388-022-02492-7

Cited by 12 publications

(12 citation statements)

References 46 publications

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“…The enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), the effector subunit of the PRC2 polycomb complex, which is recruited by Snail to catalyze the H3K27me3, thereby inhibiting E-cadherin during EMT [185]. EZH2 overexpressed in a wide variety of cancers with an active EMT [186][187][188][189][190][191][192] and cooperated with signal transducer and activator of transcription 3 (STAT3) to regulate MHC class I antigen processing in melanoma, which mediated immune responses [193]. Furthermore, in airway fibrotic diseases, ZEB1 enhanced the catalytic activity of EZH2 in epigenetic way to silence IRF1 expression especially in mesenchymal transitioned cells, associated with inhibiting the protective mucosal interferon (IFN)-I and III production [145].…”

Section: Epigenetic Alterationsmentioning

confidence: 99%

Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy

Zhang

Dijke

2023

Cell Mol Immunol

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Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, most patients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-to-mesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistance in cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsic mechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulate tumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects to enhance the ICB response for therapeutic gain in cancer patients.

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Section: Epigenetic Alterationsmentioning

confidence: 99%

Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy

Zhang

Dijke

2023

Cell Mol Immunol

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“…These include MHC Class 1b antigen processing genes and autophagy regulators. Functionally, the Ezh2 Y641F -Stat3 interaction mediated the recruitment of cytotoxic CD8+ T cells to the melanoma tumor microenvironment, which slowed down in vivo tumor growth (49). This was the first report of an enhanced non-canonical interaction between the Ezh2 Y641F mutant and a non-histone protein, suggesting that perhaps this is an important aspect of the oncogenic activity of EZH2 in cancers with Y641 mutations (7,8).…”

Section: Cell-intrinsic and Cell-extrinsic Effects Of An Ezh2-stat3 I...mentioning

confidence: 85%

“…In melanoma, EZH2 is either amplified, overexpressed or mutated at Tyrosine 641 (Y641), a hotspot mutation within the methyltransferase domain which creates a hyperactive and neomorphic protein (19). To understand the mechanisms of the oncogenic activity of this mutant, we recently investigated potential non-canonical interactions in melanoma and found that in mouse melanoma cells, mutant Ezh2 Y641F protein interacts directly with and methylates Stat3 protein (49). We found that the interaction between Ezh2 and Stat3 was highly enriched in the presence of mutant Ezh2 Y 6 4 1 F protein, which exhibits increased methyltransferase activity, suggesting that this interaction is d e p e n d e n t o n E z h 2 ' s activity.…”

Section: Cell-intrinsic and Cell-extrinsic Effects Of An Ezh2-stat3 I...mentioning

confidence: 99%

Non-canonical functions of EZH2 in cancer

Zimmerman,

Lin,

Souroullas

2023

Front. Oncol.

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Mutations in chromatin modifying genes frequently occur in many kinds of cancer. Most mechanistic studies focus on their canonical functions, while therapeutic approaches target their enzymatic activity. Recent studies, however, demonstrate that non-canonical functions of chromatin modifiers may be equally important and therapeutically actionable in different types of cancer. One epigenetic regulator that demonstrates such a dual role in cancer is the histone methyltransferase EZH2. EZH2 is a core component of the polycomb repressive complex 2 (PRC2), which plays a crucial role in cell identity, differentiation, proliferation, stemness and plasticity. While much of the regulatory functions and oncogenic activity of EZH2 have been attributed to its canonical, enzymatic activity of methylating lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark, recent studies suggest that non-canonical functions that are independent of H3K27me3 also contribute towards the oncogenic activity of EZH2. Contrary to PRC2’s canonical repressive activity, mediated by H3K27me3, outside of the complex EZH2 can directly interact with transcription factors and oncogenes to activate gene expression. A more focused investigation into these non-canonical interactions of EZH2 and other epigenetic/chromatin regulators may uncover new and more effective therapeutic strategies. Here, we summarize major findings on the non-canonical functions of EZH2 and how they are related to different aspects of carcinogenesis.

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“…Not only in HCC patients, these four genes have been found to be associated with various other types of malignancies. High levels of EZH2 are not only associated with breast cancer tumor immune response [21] , Ezh2 also acts with Stat3 as a transcriptional activator to alter the tumor immune response in melanoma [22] . G6PD is highly expressed in renal cell carcinoma, and high expression affects the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Cellular Senescence-Related Genes: Predicting Prognosis in hepatocellular carcinoma

Wang

et al. 2023

Preprint

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Recent studies have shown no significant improvement in the high incidence and low cure rates of hepatocellular carcinoma (HCC). Surgery and liver transplantation are the primary means of prolonging survival in patients with HCC. however, patients with HCC have low surgical resection rates, and even when radical surgical resection is obtained, the 5-year postoperative recurrence rate remains high, the prognosis is poor, and additional therapeutic options are urgently needed. There is increasing evidence that cellular senescence is associated with human cancers. The purpose of this study was to develop a risk model associated with cellular senescence to predict the prognosis of HCC and to search for potential strategies to treat HCC. The genome associated with cellular senescence was obtained from the CellAge website. transcriptomic data and clinical data for HCC were obtained from the Cancer Genome Atlas database (TCGA).

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Ezh2Y641F mutations co-operate with Stat3 to regulate MHC class I antigen processing and alter the tumor immune response in melanoma

Cited by 12 publications

References 46 publications

Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy

Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy

Non-canonical functions of EZH2 in cancer

Cellular Senescence-Related Genes: Predicting Prognosis in hepatocellular carcinoma

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