Epigenetic reprogramming by tumor-derived EZH2 gain-of-function mutations promotes aggressive 3D cell morphologies and enhances melanoma tumor growth

Barsotti, Anthony M.; Ryskin, Michael; Zhong, Wenyan; Zhang, Weiguo; Giannakou, Andreas; Loreth, Christine; Diesl, Veronica; Follettie, Maximillian T.; Golas, Jonathan; Lee, Michelle; Nichols, Timothy C.; Fan, Conglin; Li, Gang; Dann, Stephen G.; Fantin, Valeria R.; Arndt, Kim; Verhelle, Dominique; Rollins, Robert A.

doi:10.18632/oncotarget.2758

Cited by 41 publications

(36 citation statements)

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“…2F). Our data, together with recent publications in additional indications such as melanoma (21), breast cancer (40), renal cell carcinoma (41), cervical cancer (23), and oral squamous carcinoma (42) further indicates regulation of EMT and/or ECM (extracellular matrix) adhesion signaling as a fundamental feature of EZH2-mediated malignant reprogramming in cancer.…”

Section: Discussionsupporting

confidence: 77%

“…The inhibitor E7438 has shown efficacy in SMARCB1-mutant Rhabdoid tumors (16) and as well as GSK126 and other reported EZH2 inhibitors (17,18), in EZH2-mutant non-Hodgkin lymphoma (19) where activating mutations are described (20). In addition, effects of EZH2 inhibitors in melanoma (21) (26). In this study, we propose that EZH2 plays an important role in multiple myeloma development and progression.…”

Section: Introductionmentioning

confidence: 68%

“…A potential limitation of our proliferation results could be the experimental assay system used. Three-dimensional cultures approximating physiologic conditions have been proposed for EZH2 inhibitors to fully cover potential effects of epigenetic reprogramming (21,37). Nevertheless, our gene expression profiling after loss of global H3K27me3 is different for cell lines having comparable genetic alterations.…”

Section: Discussionmentioning

confidence: 99%

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EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

Hernando

Gelato

Lesche

et al. 2016

Molecular Cancer Therapeutics

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Multiple myeloma is a plasma cell malignancy characterized by marked heterogeneous genomic instability including frequent genetic alterations in epigenetic enzymes. In particular, the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in multiple myeloma. EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a master transcriptional regulator of differentiation. EZH2 catalyzes methylation of lysine 27 on histone H3 and its deregulation in cancer has been reported to contribute to silencing of tumor suppressor genes, resulting in a more undifferentiated state, and thereby contributing to the multiple myeloma phenotype. In this study, we propose the use of EZH2 inhibitors as a new therapeutic approach for the treatment of multiple myeloma. We demonstrate that EZH2 inhibition causes a global reduction of H3K27me3 in multiple myeloma cells, promoting reexpression of EZH2-repressed tumor suppressor genes in a subset of cell lines. As a result of this transcriptional activation, multiple myeloma cells treated with EZH2 inhibitors become more adherent and less proliferative compared with untreated cells. The antitumor efficacy of EZH2 inhibitors is also confirmed in vivo in a multiple myeloma xenograft model in mice. Together, our data suggest that EZH2 inhibition may provide a new therapy for multiple myeloma treatment and a promising addition to current treatment options. Mol Cancer Ther; 15(2); 287-98. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

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EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

Hernando

Gelato

Lesche

et al. 2016

Molecular Cancer Therapeutics

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“…Recent studies have identified reversible H3K27me3 levels in response to aberrant EZH2 activity in melanoma suggesting suitability for pharmacological targeting [10], [11], [12], [13], [14]. In particular our recent studies have shown that small molecule inhibitors of EZH2 could induce cell cycle arrest and apoptosis of melanoma cells harboring somatic mutations of EZH2 [14].…”

Section: Introductionmentioning

confidence: 92%

Somatic Copy Number Amplification and Hyperactivating Somatic Mutations of EZH2 Correlate With DNA Methylation and Drive Epigenetic Silencing of Genes Involved in Tumor Suppression and Immune Responses in Melanoma

et al. 2016

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The epigenetic modifier EZH2 is in the center of a repressive complex controlling differentiation of normal cells. In cancer EZH2 has been implicated in silencing tumor suppressor genes. Its role in melanoma as well as target genes affected by EZH2 are poorly understood. In view of this we have used an integrated systems biology approach to analyze 471 cases of skin cutaneous melanoma (SKCM) in The Cancer Genome Atlas (TCGA) for mutations and amplifications of EZH2. Identified changes in target genes were validated by interrogation of microarray data from melanoma cells treated with the EZH2 inhibitor GSK126. We found that EZH2 activation by mutations, gene amplification and increased transcription occurred in about 20% of the cohort. These alterations were associated with significant hypermethylation of DNA and significant downregulation of 11% of transcripts in patient RNASeq data. GSK126 treatment of melanoma lines containing EZH2 activation reversed such transcriptional repression in 98 candidate target genes. Gene enrichment analysis revealed genes associated with tumor suppression, cell differentiation, cell cycle inhibition and repression of metastases as well as antigen processing and presentation pathways. The identified changes in EZH2 were associated with an adverse prognosis in the TCGA dataset. These results suggest that inhibiting of EZH2 is a promising therapeutic avenue for a substantial fraction of melanoma patients.

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“…A687V is another gainof-function (GOF) mutation discovered in lymphoma, it substitutes Alanine 687 with Valine, and it is similar to other mutations since enhances EZH2 ability to perform dimethylations, whereas the ability of catalyzing trimethylations remains the same [80] . Parallel mutations have been discovered also in melanoma, where they contribute to the promotion of tumor growth [81,82] .…”

Section: Mutationsmentioning

confidence: 99%

Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

Marchesi

Bagella

2016

WJCO

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Polycomb group proteins represent a global silencing system involved in development regulation. In specific, they regulate the transition from proliferation to differentiation, contributing to stem-cell maintenance and inhibiting an inappropriate activation of differentiation programs. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2, which induces transcriptional inhibition through the tri-methylation of histone H3, an epigenetic change associated with gene silencing. EZH2 expression is high in precursor cells while its level decreases in differentiated cells. EZH2 is upregulated in various cancers with high levels associated with metastatic cancer and poor prognosis. Indeed, aberrant expression of EZH2 causes the inhibition of several tumor suppressors and differentiation genes, resulting in an uncontrolled proliferation and tumor formation. This editorial explores the role of Polycomb repressive complex 2 in cancer, focusing in particular on EZH2. The canonical function of EZH2 in gene silencing, the non-canonical activities as the methylation of other proteins and the role in gene transcriptional activation, were summarized. Moreover, mutations of EZH2, responsible for an increased methyltransferase activity in cancer, were recapitulated. Finally, various drugs able to inhibit EZH2 with different mechanism were described, specifically underscoring the effects in several cancers, in order to clarify the role of EZH2 and understand if EZH2 blockade could be a new strategy for developing specific therapies or a way to increase sensitivity of cancer cells to standard therapies.

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Epigenetic reprogramming by tumor-derived EZH2 gain-of-function mutations promotes aggressive 3D cell morphologies and enhances melanoma tumor growth

Cited by 41 publications

References 50 publications

EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

Somatic Copy Number Amplification and Hyperactivating Somatic Mutations of EZH2 Correlate With DNA Methylation and Drive Epigenetic Silencing of Genes Involved in Tumor Suppression and Immune Responses in Melanoma

Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

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