The molecular mechanisms and therapeutic potential of EZH2 in breast cancer

Adibfar, Sara; Elveny, Marischa; Kashikova, Hadisha Sh.; Михайлова, М. В.; Farhangnia, Pooya; Vakili-Samiani, Sajjad; Tarokhian, Hanieh; Jadidi‐Niaragh, Farhad

doi:10.1016/j.lfs.2021.120047

Cited by 16 publications

(6 citation statements)

References 138 publications

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“…Therefore, these analyses support that EZH2 functions as a transcriptional repressor of the mesenchymal gene expression program in human breast cancer tumours. In agreement with previous reports 1, 13 , high expression of EZH2 was associated with poor survival probability in our patient cohort (median survival, high: 132.3 months, low: 172.9 months) (Figure 3C). Thus, we concluded that augmented expression of EZH2 is associated to reduced expression of EZH2-target mesenchymal genes in breast cancer tumours and that high levels of EZH2 expression are associated with poor survival.…”

Section: Resultssupporting

confidence: 93%

EZH2 represses mesenchymal genes and upholds the epithelial state of breast carcinoma cells

Gallardo

Belmonte-Reche

Molina

et al. 2023

Preprint

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Emerging studies support that the Polycomb Repressive Complex 2 (PRC2) regulates phenotypic changes of cancer cells by modulating their shifts among metastable states within the epithelial and mesenchymal spectrum. This new role of PRC2 in cancer has been recently proposed to stem from the ability of its catalytic subunit EZH2 to bind and modulate the transcription mesenchymal genes during epithelial-mesenchymal transition (EMT) in lung cancer cells. Here, we asked whether this mechanism is conserved across different types of carcinomas. By combining TGF-β-mediate reversible induction of epithelial to mesenchymal transition and pharmacological inhibition of EZH2 activity we demonstrate that EZH2 represses a large set of mesenchymal genes and favours the residence of breast cancer cells towards the more epithelial spectrum during EMT. In agreement, analysis of human patient samples support that EZH2 is required to efficiently repress mesenchymal genes in breast cancer tumours. Our results indicate that PRC2 operates through similar mechanisms in breast and lung cancer cells, supporting that PRC2-mediated direct transcriptional modulation of the mesenchymal gene expression program is a conserved molecular mechanism underlying cell dissemination across human carcinomas.

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Section: Resultssupporting

confidence: 93%

EZH2 represses mesenchymal genes and upholds the epithelial state of breast carcinoma cells

Gallardo

Belmonte-Reche

Molina

et al. 2023

Preprint

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“…It is generally accepted that effective driver genes could play essential roles during the tumorigenesis and development of cancer ( Dawson et al, 2013 ; Martínez-Jiménez et al, 2020 ). However, till now, only a limited number of gene drivers, such as ER ( Jensen and DeSombre, 1973 ), HER2( Slamon et al, 1987 ) and EZH2 ( Adibfar et al, 2021 ; Yi et al, 2021 ; Yi et al, 2022 ), have been fully validated as targetable oncogenic drivers of BRCA. In the current study, CHEK1 and UBE2C were newly identified as hub genes and potential therapeutic targets of BRCA with the help of WCGNA, TIMER and other powerful bioinformatic tools.…”

Section: Discussionmentioning

confidence: 99%

Integrative Bioinformatics Analysis Reveals CHEK1 and UBE2C as Luminal A Breast Cancer Subtype Biomarkers

Liu

Chen

et al. 2022

Front. Genet.

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In light of the limited number of targetable oncogenic drivers in breast cancer (BRCA), it is important to identify effective and druggable gene targets for the treatment of this devastating disease. Herein, the GSE102484 dataset containing expression profiling data from 683 BRCA patients was re-analyzed using weighted gene co-expression network analysis (WGCNA). The yellow module with the highest correlation to BRCA progression was screened out, followed by functional enrichment analysis and establishment of a protein–protein interaction (PPI) network. After further validation through survival analysis and expression evaluation, CHEK1 and UBE2C were finally identified as hub genes related to the progression of BRCA, especially the luminal A breast cancer subtype. Notably, both hub genes were found to be dysregulated in multiple types of immune cells and closely correlated with tumor infiltration, as revealed by Tumor Immune Estimation Resource (TIMER) along with other bioinformatic tools. Construction of transcription factors (TF)-hub gene network further confirmed the existence of 11 TFs which could regulate both hub genes simultaneously. Our present study may facilitate the invention of targeted therapeutic drugs and provide novel insights into the understanding of the mechanism beneath the progression of BRCA.

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“…EZH2 is a histone H3 lysine 27 methyltransferase with a component of Polycomb repressive complex 2 (PRC2), and it acts as a downregulator for various targeted genes [113][114][115]. EZH2 is highly upregulated in various malignancies such as melanoma and plays a vital role in cell growth and proliferation; therefore, EH2 is highlighted as an anti-tumor treatment [116][117][118]. EZH2 plays a role in the anti-tumor response of macrophages against mesothelioma cells [119].…”

Section: Ezh2 Reduces Pd-1 Expressionmentioning

confidence: 99%

Epigenetic Modification of PD-1/PD-L1-Mediated Cancer Immunotherapy against Melanoma

Nanamori

Sawada

2022

IJMS

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Malignant melanoma is one of the representative skin cancers with unfavorable clinical behavior. Immunotherapy is currently used for the treatment, and it dramatically improves clinical outcomes in patients with advanced malignant melanoma. On the other hand, not all these patients can obtain therapeutic efficacy. To overcome this limitation of current immunotherapy, epigenetic modification is a highlighted issue for clinicians. Epigenetic modification is involved in various physiological and pathological conditions in the skin. Recent studies identified that skin cancer, especially malignant melanoma, has advantages in tumor development, indicating that epigenetic manipulation for regulation of gene expression in the tumor can be expected to result in additional therapeutic efficacy during immunotherapy. In this review, we focus on the detailed molecular mechanism of epigenetic modification in immunotherapy, especially anti-PD-1/PD-L1 antibody treatment for malignant melanoma.

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The molecular mechanisms and therapeutic potential of EZH2 in breast cancer

Cited by 16 publications

References 138 publications

EZH2 represses mesenchymal genes and upholds the epithelial state of breast carcinoma cells

EZH2 represses mesenchymal genes and upholds the epithelial state of breast carcinoma cells

Integrative Bioinformatics Analysis Reveals CHEK1 and UBE2C as Luminal A Breast Cancer Subtype Biomarkers

Epigenetic Modification of PD-1/PD-L1-Mediated Cancer Immunotherapy against Melanoma

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