Overexpression of histone deacetylases in cancer cells is controlled by interplay of transcription factors and epigenetic modulators

Yang, Hui; Salz, Tal; Zajac-Kaye, Maria; Liao, Daiqing; Huang, Suming; Qiu, Yi

doi:10.1096/fj.14-250654

Cited by 58 publications

(53 citation statements)

References 54 publications

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“…H3K4me3 is enriched at the TSS of transcriptionally active genes (16)(17)(18)(19), although whether this modification is a passive mark for active transcription or plays an active role in promoting transcription is currently under debate. Nevertheless, our group and others have observed both global and local changes in H3K4me3 at promoters of genes with cancer-promoting activity, in cancer cells (14,25,26,53,54). Methylation of H3K4 is primarily catalyzed by TrxG members, with the modification of H3K4me3 chiefly catalyzed by hSETD1A (26,27,(55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 80%

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Salz

Deng

Pampo

et al. 2015

Molecular Cancer Research

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Epigenetic alteration is a hallmark of all cancers. Such alterations lead to modulation of fundamental cancer-related functions, such as proliferation, migration, and invasion. In particular, methylation of Histone H3 Lysine 4 (H3K4), a histone mark generally associated with transcriptional activation, is altered during progression of several human cancers. While the depletion of H3K4 demethylases promotes breast cancer metastasis, the effect of H3K4 methyltransferases on metastasis is not clear. Nevertheless, gene duplications in the human SETD1A (hSETD1A) H3K4 methyltransferase are present in almost half of breast cancers. Herein, expression analysis determined that hSETD1A is upregulated in multiple metastatic human breast cancer cell lines and clinical tumor specimens. Ablation of hSETD1A in breast cancer cells led to a decrease in migration and invasion in vitro and to a decrease in metastasis in nude mice. Furthermore, a group of matrix metalloproteinases (including MMP2, MMP9, MMP12, MMP13, and MMP17) were identified which were downregulated upon depletion of hSETD1A and demonstrated a decrease in H3K4me3 at their proximal promoters based on chromatin immunoprecipitation analysis. These results provide evidence for a functional and mechanistic link among hSETD1A, MMPs, and metastasis in breast cancer, thereby supporting an oncogenic role for hSETD1A in cancer.Implications: This study reveals that hSETD1A controls tumor metastasis by activating MMP expression and provides an epigenetic link among hSETD1A, MMPs, and metastasis of breast cancer.

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Section: Discussionmentioning

confidence: 80%

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Salz

Deng

Pampo

et al. 2015

Molecular Cancer Research

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“…Growing evidence demonstrates that HDACs are overexpressed in various cancers, such as colon cancer [30], breast cancer [31], prostate cancer [32] and acute myeloid leukemia [33]. Dysregulation of chromatin modification by HDACs contributes to aberrant gene expression in human cancers.…”

Section: Hdacs As Targets For Cancer Therapymentioning

confidence: 99%

Epigenetic Modulation with Histone Deacetylase Inhibitors in Combination with Immunotherapy

2015

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Understanding the contribution of dysregulated gene silencing to epigenomic alterations in cancer development provides the rationale for the use of epigenetic modulators, such as histone deacetylase (HDAC) inhibitors, in cancer therapy. HDAC inhibitors have been approved as single agents for cutaneous and peripheral T-cell lymphoma and have shown promising activity in reversing therapy resistance in other tumor types. The effects of HDAC inhibitors on immune modulation have created a recent interest in their potential role in immunotherapy. This review describes the current understanding on integrating HDAC inhibitors into various immunotherapeutic approaches, such as cancer vaccines, adoptive T-cell transfer and immune checkpoint inhibitors. Furthermore, it summarizes promising treatment strategies in epigenetic immune priming from clinical trials that are currently underway.

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“…Malignant cells are characterized by overexpression of histone deacetylases (HDACs) and a global reduction in levels of histone acetylation and by significant dysregulation of histone methyltransferases (HMTs) and histone demethylases [1,[12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Specific combinations of the chromatin-modifying enzyme modulators significantly attenuate glioblastoma cell proliferation and viability while exerting minimal effect on normal adult stem cells growth

Alexanian¹,

Huang

2015

Tumor Biol.

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The discoveries of recent decade showed that all critical changes in cancer cells, such as silencing of tumor-suppressor genes and activation of oncogenes, are caused not only by genetic but also by epigenetic mechanisms. Although epigenetic changes are somatically heritable, in contrast to genetic changes, they are potentially reversible, making them good targets for therapeutic intervention. Covalent modifications of chromatin such as methylation and acetylation of histones and methylation of DNA are the important components of epigenetic machinery. In this study, we investigated the effect of different modulators of DNA and histone covalent-modifying enzymes on the proliferation and viability of normal adult stem cells, such as human bone marrow mesenchymal stem cells (hMSCs), and on malignant tumor cells, such as glioblastoma (GB) D54 cells. Results demonstrated that specific combinations of histone methyltransferases and deacetylases inhibitors significantly attenuated D54 cells viability but having only a small effect on hMSCs growth. Taken together, these studies suggest that specific combinations of histone covalent modifiers could be an effective treatment option for the most aggressive type of primary brain tumors such as glioblastoma multiforme.

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Overexpression of histone deacetylases in cancer cells is controlled by interplay of transcription factors and epigenetic modulators

Cited by 58 publications

References 54 publications

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

Epigenetic Modulation with Histone Deacetylase Inhibitors in Combination with Immunotherapy

Specific combinations of the chromatin-modifying enzyme modulators significantly attenuate glioblastoma cell proliferation and viability while exerting minimal effect on normal adult stem cells growth

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