Elevated expression of a pharmacologic Polycomb signature predicts poor prognosis in gastric and breast cancer

Clermont, Pier-Luc; Fornaro, Lorenzo; Crea, Francesco

doi:10.2217/epi-2017-0074

Cited by 6 publications

(5 citation statements)

References 41 publications

(44 reference statements)

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“…Elevated levels of Ezh2 protein have been reported in prostate and breast cancer (Valk-Lingbeek et al, 2004). Furthermore, recent studies have stated that Ezh2 overexpression is associated with aggressiveness and progression of different cancer types such as prostate, breast, bladder, and endometrial cancer, as well as melanoma (Bachmann et al, 2006;Clermont et al, 2017).…”

Section: Epigenetic Status In Cancermentioning

confidence: 99%

“…The 3-deazaneplanocin A (DZNep), a small molecule inhibitor of Ezh2, decreases global H3K27 trimethylation, and its overexpression is associated with aggressiveness of several cancers such as prostate, breast, and bladder, as well as melanoma (Bachmann et al, 2006;Clermont et al, 2017). It has been shown that DZNep causes inhibition of proliferation and migration in mesothelioma (Kemp et al, 2012).…”

Section: Targeting Histone Modifications In Cancer Therapymentioning

confidence: 99%

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Key actors in cancer therapy: epigenetic modifiers

Akar¹,

Selvi²,

Ulukaya³

et al. 2019

Turk J Biol

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Epigenetic reprogramming plays a crucial role in the tumorigenicity and maintenance of tumor-specific gene expression that especially occurs through DNA methylation and/or histone modifications. It has well-defined mechanisms. It is known that alterations in the DNA methylation pattern and/or the loss of specific histone acetylation/methylation markers are related to several hallmarks of cancer, such as drug resistance, stemness, epithelial-mesenchymal transition, and metastasis. It has also recently been highlighted that epigenetic alterations are critical for the regulation of the stemlike properties of cancer cells (tumor-initiating cells; cancer stem cells). Cancer stem cells are thought to be responsible for the recurrence of cancer which makes the patient return to the clinic with metastatic tumor tissue. Hence, the dysregulation of epigenetic machinery represents potential new therapeutic targets. Therefore, compounds with epigenetic activities have become crucial for developing new therapy regimens (e.g., antimetastatic agents) in the fight against cancer. Here, we review the epigenetic modifiers that have already been used in the clinic and/or in clinical trials, related preclinical studies in cancer therapy, and the smart combination strategies that target cancer stem cells along with the other cancer cells. The emerging role of epitranscriptome (RNA epigenetic) in cancer therapy has also been included in this review as a new avenue and potential target for the better management of cancer-beneficial epigenetic machinery.

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Section: Epigenetic Status In Cancermentioning

confidence: 99%

Section: Targeting Histone Modifications In Cancer Therapymentioning

confidence: 99%

Key actors in cancer therapy: epigenetic modifiers

Akar¹,

Selvi²,

Ulukaya³

et al. 2019

Turk J Biol

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show abstract

“…[7][8][9][10] Based on gene microarray analysis, several prognostic gene signatures have also been identified in gastric cancer. 2,[11][12][13][14] However, tumor samples usually have a complex composition and tissue heterogeneity. These gene expressions (RNA)-based signatures could not accurately indicate the expression level and heterogeneity among the tumor cells and were not always consistent with the expression of proteins, which are the final executors of a biological function.…”

Section: Introductionmentioning

confidence: 99%

An integrated classifier improves prognostic accuracy in non-metastatic gastric cancer

et al. 2020

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The American Joint Committee on Cancer (AJCC) staging system is insufficiently prognostic for gastric cancer (GC) patients and complementary factors are in urgent need. Here we aimed to develop a comprehensive model, consisting of both immune signatures and cancer signaling molecules, which was expected to accurately improve survival prediction in non-metastatic gastric cancer (GC). We first validated the prognostic value of a combination of 18 immune features and 52 cancer-signaling molecules in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Then, their expression and distribution were analyzed in consecutive 1180 GC patients using immunohistochemistry. We developed and validated a novel protein-based prognostic classifier using CDH1, an epithelial-mesenchymal transition (EMT) marker, and five immune features (CD3, CD4, CD274, GZMB, and PAX5) by Cox regression model with group LASSO penalty. We observed significant differences in the overall survival of the highand low-prognostic risk groups (66.8% VS 27.0%, P < .001). A combination of this classifier with age and pTNM stage had better prognostic value than pTNM alone. The model was further validated in both treatment-naive patients and those treated with neoadjuvant chemotherapy. Moreover, GC patients with high-risk score exhibited a favorable prognosis to adjuvant chemotherapy. This integrated classifier could be automatically analyzed and effectively predict survival of GC patients and may provide a new clinically applicable strategy to identify patients who are more likely to benefit from adjuvant chemotherapy.

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“…One of its most prominent mechanisms of action is the silencing of many cancer-related genes, thereby promoting histone H3 lysine 27 trimethylation (H3K27me3) of target gene promoters [9]. Recently, reports have shown EZH2 frequently overexpressed in several human epithelial cancers, including prostate cancer [10], breast cancer [11], gastric cancer [11], non-small-cell lung cancer [12], esophageal cancer [13], melanomas [9], oral cancer [14], and endometrial carcinomas [15]; it is additionally associated with increased tumor cell proliferation and exacerbated outcomes [16]. 3-Deazaneplanocin A (DZNep) reportedly downregulates EZH2 and inhibits H3K27me3 [17].…”

Section: Introductionmentioning

confidence: 99%

Aberrant Epigenetic Regulation in Head and Neck Cancer Due to Distinct EZH2 Overexpression and DNA Hypermethylation

Mochizuki

Misawa

Kawasaki

et al. 2018

IJMS

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Enhancer of Zeste homologue 2 (EZH2) overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibition of EZH2 is a potentially effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence (p < 0.001) and the methylation index of tumor suppressor genes (p < 0.05). DNMT3A was significantly upregulated upon EZH2 upregulation (p = 0.043). Univariate analysis revealed that EZH2 upregulation was associated with poor disease-free survival (log-rank test, p < 0.001). In multivariate analysis, EZH2 upregulation was evaluated as a significant independent prognostic factor of disease-free survival (hazard ratio: 2.085, 95% confidence interval: 1.390–3.127; p < 0.001). Cells treated with RNA interference and DZNep, an EZH2 inhibitor, showed the most dramatic changes in expression, accompanied with a reduction in the growth and survival of FaDu cells. These findings suggest that EZH2 upregulation is correlated with tumor aggressiveness and adverse patient outcomes in HNSCC. Evaluation of EZH2 expression might help predict the prognosis of HNSCC patients.

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Elevated expression of a pharmacologic Polycomb signature predicts poor prognosis in gastric and breast cancer

Cited by 6 publications

References 41 publications

Key actors in cancer therapy: epigenetic modifiers

Key actors in cancer therapy: epigenetic modifiers

An integrated classifier improves prognostic accuracy in non-metastatic gastric cancer

Aberrant Epigenetic Regulation in Head and Neck Cancer Due to Distinct EZH2 Overexpression and DNA Hypermethylation

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