EZH2 Is Essential for Glioblastoma Cancer Stem Cell Maintenance

Suvà, Mario-Luca; Riggi, Nicolò; Janiszewska, Michalina; Radovanović, Ivan; Provero, Paolo; Stehle, Jean-Christophe; Baumer, Karine; Bitoux, Marie-Aude Le; Marino, Denis; Cironi, Luisa; Márquez, Víctor E.; Clément, Virginie; Stamenkovic, Ivan

doi:10.1158/0008-5472.can-09-1622

Cited by 447 publications

(423 citation statements)

References 27 publications

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“…In addition Wang et al [8], revealed that EZH2 expression correlated with tumor aggressiveness across all cancer types and Li et al [36], showed that the most frequently overexpressed PcG gene in GBMs was EZH2 in (98.6%) and suggested that EZH2 a hopeful therapeutic target in GBMs because of the extremely high frequency of overexpression. Also similar results were optained by Suvà et al [37] and Orzan et al [38]. As regard other clinicopathologic characteristics of astrocytoma (age at diagnosis, Lobna A. Abdelsalam ; et al….…”

Section: Bmi1 and Ezh2 Expression In Astrocytoma And Non-neoplastic Bsupporting

confidence: 76%

Prognostic Value of Combined Immunohistochemical Expression of Bmi1 and Ezh2 in Astrocytoma

Abdelsalam

Ali

ElKashishy

et al. 2017

Zagazig University Medical Journal

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Background: Although current improvements in surgery, chemotherapy and radiotherapy, the still survival of astrocytoma's patient is poor. It is assumed that the combined expression of BMI1 and EZH2 may be associated with malignant transformation of astrocytomas and also it may reveal the biological aggressiveness of this disease. Aim of work: assessment the value of the combined immunohistochemical expression of BMI1 and EZH2 and their correlation with the clinicopathological characters and prognosis in astrocytoma patient. Subjects & Methods: BMI1 and EZH2 expressions were evaluated using immunohistochemical staining in 70 patients 40 cases with astrocytomas and 30 cases of non-neoplastic brain tissue. The relationship between their expressions and clinicopathological factors were analyzed. Results: A significant difference (P<0.002) between expression of BMI1 and EZH2 in astrocytoma compared to corresponding non-neoplastic brain tissue. A significant association was found between high expression of BMI1 and EZH2 and WHO high grades in astrocytomas. No statistically significant association was found between BMI1 or EZH2 with gender of patients, age at diagnosis, site and size of tumor (P > 0.05). The spearman correlation analysis revealed a significant positive association between BMI1 and EZH2 expressions (r = 0.311; P=0.05) revealing direct relationship between BMI1 and EZH2. Conclusions: BMI1 and EZH2 were involved in astrocytoma malignant transformation and poor prognosis in astrocytoma particularly glioblastoma.

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Section: Bmi1 and Ezh2 Expression In Astrocytoma And Non-neoplastic Bsupporting

confidence: 76%

Prognostic Value of Combined Immunohistochemical Expression of Bmi1 and Ezh2 in Astrocytoma

Abdelsalam

Ali

ElKashishy

et al. 2017

Zagazig University Medical Journal

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“…EZH2-silenced cells give rise to slow growing tumors, as has been previously shown (18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 57%

“…EZH2 promotes cancer cell proliferation, anchorage-independent growth and invasiveness (13,(17)(18)(19). In vivo, EZH2 inhibition reduces tumor growth rates to various extents (18)(19)(20)(21). However, the functions of EZH2 in controlling cancer cell differentiation remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

EZH2 promotes a bi-lineage identity in basal-like breast cancer cells

et al. 2012

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The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitorassociated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a "bi-lineage" differentiation state, in which cells co-express basal-and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal-progenitor gene expression. GATA3 levels increase upon EZH2 silencing, mediating a decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition.

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“…41,42 As EZH2 depletion simultaneously abolishes both DNA damage-induced G1 and G2/M checkpoints, therapeutic targeting EZH2, as demonstrated here as a proof of concept using DZNep, in combination with standard chemotherapy, may provide a unique advantage over the existing approaches for treatment of cancer patients carrying wild-type or mutant p53. Furthermore, given a potential role of EZH2 or PRC2 in maintenance of cancer stem cells 43,44 and a recent finding showing that DNA damage-activated p21 is required for self-renewal of leukemia stem cells, 45 EZH2 inhibition might also have the potential for overcoming chemoresistance phenotype typically seen in cancer stem cells, and thereby preventing tumor recurrence after chemotherapy. Plasmids and stable cell lines.…”

Section: Discussionmentioning

confidence: 99%

Polycomb protein EZH2 regulates cancer cell fate decision in response to DNA damage

Lee

Qiao

et al. 2011

Cell Death Differ

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Polycomb protein histone methyltransferase enhancer of Zeste homologe 2 (EZH2) is frequently overexpressed in human malignancy and is implicated in cancer cell proliferation and invasion. However, it is largely unknown whether EZH2 has a role in modulating DNA damage response. Here, we show that EZH2 is an important determinant of cell fate decision in response to genotoxic stress. EZH2 depletion results in abrogation of both cell cycle G1 and G2/M checkpoints, directing DNA damage response toward predominant apoptosis in both p53-proficient and p53-deficient cancer cells, but not in normal cells. Mechanistically, EZH2 regulates DNA damage response in p53 wild-type cells mainly through transcriptional repression of FBXO32, which binds to and directs p21 for proteasome-mediated degradation, whereas it affects p53-deficient cells through regulating Chk1 activation by a distinct mechanism. Furthermore, pharmacological depletion of EZH2 phenocopies the effects of EZH2 knockdown on cell cycle checkpoints and apoptosis. These data unravel a crucial role of EZH2 in determining the cancer cell outcome following DNA damage and suggest that therapeutic targeting oncogenic EZH2 might serve as a strategy for improving conventional chemotherapy in a given malignancy. Cell Death and Differentiation (2011) 18, 1771-1779; doi:10.1038/cdd.2011.48; published online 6 May 2011Following DNA damage, mammalian cells activate cell cycle checkpoint mechanisms to induce cell cycle arrest and protect cells from apoptosis. 1 The interconnections between the pathways regulating the cell cycle checkpoints and apoptosis dictate the cellular outcome to DNA damage, 2 but whether these pathways are differentially regulated by oncogenic lesions in tumor cells to allow cancer-specific perturbation is poorly understood. Inhibition of key cell cycle checkpoint regulators such as cyclin-dependent kinase inhibitor p21 and Chk1/2 have been shown to increase the sensitivity to DNA damage in p53-proficient or p53-deficient cancer cells, respectively. 3-14 A treatment strategy to simultaneously abrogate both G1 and G2/M checkpoint and thus sensitizing both p53 wild-type and mutant tumors has yet to be developed.Polycomb protein enhancer of Zeste homologe 2 (EZH2) is a histone methyltransferase that is frequently overexpressed in a wide variety of human malignancies, 15,16 and is implicated in cell proliferation, invasion and metastasis. [17][18][19][20][21][22][23][24][25] Mechanistically, the oncogenic function of EZH2 has been attributed to associated histone H3 with trimethylated lysine 27 (H3K27Me3), leading to transcriptional repression of tumor suppressor genes, including p16(INK4a) and p19(ARF), 26 E-cadherin, 19 adrenergic receptor-b2, 27 RUNX3, 20 p57 (also called CDKN1C), 21 Bim 28 and DAB2IP. 23,24 As such, EZH2 is emerging as a crucial regulator of cell fate by affecting multiple signaling pathways. It is not clear, however, whether EZH2 overexpression in cancer cells has a role in affecting cellular response to DNA damage. This study investi...

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EZH2 Is Essential for Glioblastoma Cancer Stem Cell Maintenance

Cited by 447 publications

References 27 publications

Prognostic Value of Combined Immunohistochemical Expression of Bmi1 and Ezh2 in Astrocytoma

Prognostic Value of Combined Immunohistochemical Expression of Bmi1 and Ezh2 in Astrocytoma

EZH2 promotes a bi-lineage identity in basal-like breast cancer cells

Polycomb protein EZH2 regulates cancer cell fate decision in response to DNA damage

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