Role of EZH2 histone methyltrasferase in melanoma progression and metastasis

Mahmoud, Fade; Shields, Bradley D.; Makhoul, Issam; Hutchins, Laura F.; Shalin, Sara C.; Tackett, Alan J.

doi:10.1080/15384047.2016.1167291

Cited by 44 publications

(35 citation statements)

References 153 publications

(257 reference statements)

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“…Gene ACSL5 has been observed to be critical to the expression of tumor‐related factor MCAM, indicating its potential effect on melanoma . Gene EZH2 has been shown to contribute to the transcriptional silencing of tumor suppressor and differentiation genes and be involved in melanoma progression and metastasis . The expression of gene ATP5A1 has been detected prevalently in the cytoplasm of melanoma cells .…”

Section: Resultsmentioning

confidence: 99%

“…43 Gene EZH2 has been shown to contribute to the transcriptional silencing of tumor suppressor and differentiation genes and be involved in melanoma progression and metastasis. 44 The expression of gene ATP5A1 has been detected prevalently in the cytoplasm of melanoma cells. 45 The MSH6 expression has been observed to be absent or extremely low in benign nevi and increased in a subset of primary melanoma samples and suggested as a valuable marker to improve prognosis assessment in primary melanoma.…”

Section: Skcm Datamentioning

confidence: 99%

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Robust semiparametric gene‐environment interaction analysis using sparse boosting

2019

Statistics in Medicine

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For the pathogenesis of complex diseases, gene‐environment (G‐E) interactions have been shown to have important implications. G‐E interaction analysis can be challenging with the need to jointly analyze a large number of main effects and interactions and to respect the “main effects, interactions” hierarchical constraint. Extensive methodological developments on G‐E interaction analysis have been conducted in recent literature. Despite considerable successes, most of the existing studies are still limited as they cannot accommodate long‐tailed distributions/data contamination, make the restricted assumption of linear effects, and cannot effectively accommodate missingness in E variables. To directly tackle these problems, a semiparametric model is assumed to accommodate nonlinear effects, and the Huber loss function and Qn estimator are adopted to accommodate long‐tailed distributions/data contamination. A regression‐based multiple imputation approach is developed to accommodate missingness in E variables. For model estimation and selection of relevant variables, we adopt an effective sparse boosting approach. The proposed approach is practically well motivated, has intuitive formulations, and can be effectively realized. In extensive simulations, it significantly outperforms multiple direct competitors. The analysis of The Cancer Genome Atlas data on stomach adenocarcinoma and cutaneous melanoma shows that the proposed approach makes sensible discoveries with satisfactory prediction and stability.

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Section: Resultsmentioning

confidence: 99%

Section: Skcm Datamentioning

confidence: 99%

Robust semiparametric gene‐environment interaction analysis using sparse boosting

2019

Statistics in Medicine

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“…Therefore, EZH2 is currently considered a promising drug target, and multiple inhibitors of EZH2 have been developed, some of which are in clinical trials [ 21 ]. Moreover, recent studies have shown that EZH2 also plays a critical role in the proliferation and survival of melanoma [ 19 , 22 – 28 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of coexistence of BRAF V600E mutation and EZH2 gain specifically in melanoma as a promising target for combination therapy

Yan

et al. 2017

J Transl Med

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BackgroundCoexistence of enhancer of zeste homolog 2 (EZH2) and BRAF gene aberrations has been described in many cancer types. In this study, we aim to explore the coexistence status of BRAF V600E mutation and the copy number variation of EZH2 and explore the potential of this combination as a therapeutic target.MethodsA total of 138 cases of melanoma samples harboring BRAF V600E mutation were included, and EZH2 copy numbers were examined by QuantiGenePlex DNA Assays. Clinical pathological distinction between patient groups with or without EZH2 amplification (hereafter referred to as EZH2 gain) was statistically analyzed. The sensitivity of melanoma cell lines and patient-derived xenograft (PDX) models containing BRAF V600E mutation with or without EZH2 gain to vemurafenib (BRAF inhibitor), GSK2816126 (EZH2 inhibitor) and a combination of both agents was evaluated.ResultsIn our cohort, the coexistence rate of BRAF V600E mutation and EZH2 gain was up to 29.0%, and significant differences in overall survival and disease-free survival were found between no EZH2 copy number gain and gain groups (P = 0.038, P = 0.030), gain and high EZH2 copy number gain groups (P = 0.006, P = 0.010). Combination with BRAF and EZH2 inhibition showed better inhibitory efficacy in melanoma prevention compared with vemurafenib monotherapy. More importantly, this improved therapeutic effect was observed especially in melanoma cell lines and PDX models containing concurrently BRAF V600E mutation and EZH2 gain.ConclusionsCoexistence of BRAF V600E mutation and EZH2 gain is rather prevalent in melanoma. Our findings provided evidence for the feasibility of combination therapy with EZH2 and BRAF inhibitors in melanoma with concurrent BRAF V600E mutation and EZH2 gain.Electronic supplementary materialThe online version of this article (10.1186/s12967-017-1344-z) contains supplementary material, which is available to authorized users.

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“…Melanoma cells harbor the Y641 activating mutation within the catalytic SET domain that was first described in Diffuse large B-cell (DLBC) lymphoma. Numerous studies have identified an association between aberrant EZH2 expression and melanoma progression [38]. Although EZH2 SNVs have not been comprehensively investigated in this setting, further translational studies are warranted.…”

Section: Resultsmentioning

confidence: 99%

EZH2 Single Nucleotide Variants (SNVs): Diagnostic and Prognostic Role in 10 Solid Tumor Types

et al. 2017

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Abstract:The enhancer of zeste homolog 2 (EZH2) gene encodes a histone methyltransferase that is a catalytic subunit of the Polycomb repressive complex 2 (PRC2) group of proteins that act to repress gene expression. The EZH2 locus is rarely mutated in solid tumors and there is no comprehensive study of EZH2 single nucleotide variants (SNVs) associated with cancer susceptibility, prognosis and response to therapy. Here, for the first time, we review the functional roles of EZH2 DNA variants and propose a putative etiological role in 10 various solid tumors including: esophageal, hepatocellular, oral, urothelial, colorectal, lung and gastric cancers. In particular, we found that the C allele of the EZH2 variant rs3757441 is associated with increased EZH2 RNA expression and poorer prognosis (advanced stage) in at least two malignancies such as colorectal and hepatocellular carcinoma. This suggests that the C allele may be a functional risk variant in multiple malignant tumors. We therefore propose that the rs3757441 single nucleotide variant (SNV) be genotyped and real-time PCR assays be performed in large cohort studies in order to confirm this preliminary finding that could be useful for clinical practice.

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Role of EZH2 histone methyltrasferase in melanoma progression and metastasis

Cited by 44 publications

References 153 publications

Robust semiparametric gene‐environment interaction analysis using sparse boosting

Robust semiparametric gene‐environment interaction analysis using sparse boosting

Identification of coexistence of BRAF V600E mutation and EZH2 gain specifically in melanoma as a promising target for combination therapy

EZH2 Single Nucleotide Variants (SNVs): Diagnostic and Prognostic Role in 10 Solid Tumor Types

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