EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma

Xiao, Gang; Jin, Li-Lian; Liu, Chaoqun; Wang, Yongchun; Meng, Ya-Ming; Zhou, Zhongguo; Chen, Jing; Yu, Xing-Juan; Zhang, Yaojun; Xu, Jing; Zheng, Limin

doi:10.1186/s40425-019-0784-9

Cited by 120 publications

(97 citation statements)

References 55 publications

(58 reference statements)

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“…For example, in NSCLC patients, anti-PD-1 therapy enhanced PD-L1 promoter methylation and reduced PD-L1 expression which mediated resistance to anti-PD-1 immunotherapy Nivolumab in NSCLC patients (117). In addition, histone modifications including methylation and acetylation have been reported to modulate PD-L1 expression in some cancers (118)(119)(120)(121)(122)(123). The histone methyltransferase, enhancer of zeste 2 polycomb repressive complex 2 subunit has been shown to suppress PD-L1 expression through mediating trimethylation of the PD-L1 promoter in hepatoma cells (120).…”

Section: Epigenetic Mechanisms Modulate Pd-l1 Expressionmentioning

confidence: 99%

“…In addition, histone modifications including methylation and acetylation have been reported to modulate PD-L1 expression in some cancers (118)(119)(120)(121)(122)(123). The histone methyltransferase, enhancer of zeste 2 polycomb repressive complex 2 subunit has been shown to suppress PD-L1 expression through mediating trimethylation of the PD-L1 promoter in hepatoma cells (120). Moreover, histone deacetylases have been reported to regulate PD-L1 expression in melanoma cells (122,124,125).…”

Section: Epigenetic Mechanisms Modulate Pd-l1 Expressionmentioning

confidence: 99%

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The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment

et al. 2020

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Programmed death-ligand 1 (PD-L1) is an immune checkpoint inhibitor that binds to its receptor PD-1 expressed by T cells and other immune cells to regulate immune responses; ultimately preventing exacerbated activation and autoimmunity. Many tumors exploit this mechanism by overexpressing PD-L1 which often correlates with poor prognosis. Some tumors have also recently been shown to express PD-1. On tumors, PD-L1 binding to PD-1 on immune cells promotes immune evasion and tumor progression, primarily by inhibition of cytotoxic T lymphocyte effector function. PD-1/PD-L1-targeted therapy has revolutionized the cancer therapy landscape and has become the first-line treatment for some cancers, due to their ability to promote durable anti-tumor immune responses in select patients with advanced cancers. Despite this clinical success, some patients have shown to be unresponsive, hyperprogressive or develop resistance to PD-1/PD-L1-targeted therapy. The exact mechanisms for this are still unclear. This review will discuss the current status of PD-1/PD-L1-targeted therapy, oncogenic expression of PD-L1, the new and emerging tumor-intrinisic roles of PD-L1 and its receptor PD-1 and how they may contribute to tumor progression and immunotherapy responses as shown in different oncology models.

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Section: Epigenetic Mechanisms Modulate Pd-l1 Expressionmentioning

confidence: 99%

Section: Epigenetic Mechanisms Modulate Pd-l1 Expressionmentioning

confidence: 99%

The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment

et al. 2020

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“…These inhibitors are able to enhance the expression of several antigen presenting molecules, co-stimulatory molecules, and checkpoint ligands [8]. Other epigenetics enzymes, such as the histone methyltransferase, EZH2, have been shown to regulate the expression of PD-L1 in hepatocellular carcinoma by upregulating H3K27me3 levels on the promoters of CD274 (encoding PD-L1) and IRF1 [40]. Furthermore, BET bromodomain inhibitors have been shown to upregulate PD-L1 and MHC I expression in ovarian and prostate cancer cells [41,42].…”

Section: Epigeneticsmentioning

confidence: 99%

Epitherapy and immune checkpoint blockade: using epigenetic reinvigoration of exhausted and dysfunctional T cells to reimburse immunotherapy response

et al. 2020

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Background: Cancer cells subvert natural immunosuppression by upregulating the expression of checkpoint proteins and their ligands. For example, tumor cells expressing programmed death-ligand 1 (PD-L1) induce immune cell tolerance to cancers, thereby facilitating tumor progression. The recent clinical success of immunotherapy, particularly checkpoint blockade, represents a significant advance in cancer therapy. However, many cancers develop resistance to immunotherapies, and the underlying mechanisms and how these might be exploited to overcome resistance still need to be determined.Methods: T cell dysfunction, in part caused by chronic T cell receptor stimulation, diminishes the capacity for durable responses to checkpoint blockade. Furthermore, T cell populations are phenotypically and functionally heterogeneous, resulting in varying responses to checkpoint blockade. Recent molecular studies of T cell heterogeneity have shown that checkpoint blockade on its own does not alter the epigenetic landscape of T cells, despite epigenetic changes governing T cell phenotype.Conclusion: Here we argue that epigenetic modifiers can be used to prime and sensitize T cells to immunotherapy. Administering epitherapy in conjunction with checkpoint blockade could decrease T cell exhaustion and immunotherapy resistance in many cancer types.

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“…EZH2, as a master regulator of transcription, plays a critical role in occurrence and progression of human cancers (Kim and Roberts, 2016). EZH2 has been unraveled as a core factor in hepatocarcinogenesis, self-renewal of liver cancer stem cells (CSCs), and molecular targeted therapy (Cheng et al, 2011;Zhu et al, 2016;Xiao et al, 2019). However, the regulatory mechanism of EZH2 in oncogenic transformation remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Identification of Gene Signatures for Diagnosis and Prognosis of Hepatocellular Carcinomas Patients at Early Stage

et al. 2020

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The onset of liver cancer is insidious. Currently, there is no effective method for the early detection of hepatocellular carcinoma (HCC). Transcriptomic profiles of 826 tissue samples from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), Genotype tissue expression (GTEx), and International Cancer Genome Consortium (ICGC) databases were utilized to establish models for early detection and surveillance of HCC. The overlapping differentially expressed genes (DEGs) were screened by elastic net and robust rank aggregation (RRA) analyses to construct the diagnostic prediction model for early HCC (DP.eHCC). Prognostic prediction genes were screened by univariate cox regression and lasso cox regression analyses to construct the survival risk prediction model for early HCC (SP.eHCC). The relationship between the variation of transcriptome profile and the oncogenic risk-score of early HCC was analyzed by combining Weighted Correlation Network Analysis (WGCNA), Gene Set Enrichment Analysis (GSEA), and genome networks (GeNets). The results showed that the AUC of DP.eHCC model for the diagnosis of early HCC was 0.956 (95% CI: 0.941-0.972; p < 0.001) with a sensitivity of 90.91%, a specificity of 92.97%. The SP.eHCC model performed well for predicting the overall survival risk of HCC patients (HR = 10.79; 95% CI: 6.16-18.89; p < 0.001). The oncogenesis of early HCC was revealed mainly involving in pathways associated with cell proliferation and tumor microenvironment. And the transcription factors including EZH2, EGR1, and SOX17 were screened in the genome networks as the promising targets used for precise treatment in patients with HCC. Our findings provide robust models for the early diagnosis and prognosis of HCC, and are crucial for the development of novel targets applied in the precision therapy of HCC.

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EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma

Cited by 120 publications

References 55 publications

The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment

The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment

Epitherapy and immune checkpoint blockade: using epigenetic reinvigoration of exhausted and dysfunctional T cells to reimburse immunotherapy response

Identification of Gene Signatures for Diagnosis and Prognosis of Hepatocellular Carcinomas Patients at Early Stage

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