The role of epigenetics in the biology of multiple myeloma

Dimopoulos, Konstantinos; Gimsing, Peter; Grønbæk, Kirsten

doi:10.1038/bcj.2014.29

“…P values were calculated using ANOVA compared with vehicle ( Ã , P 0.05; ÃÃ , P 0.01 and ÃÃÃ , P 0.001). (33). We uncovered an antiproliferative activity of EZH2 inhibition in vitro in a set of multiple myeloma cell lines and translated these findings to an in vivo xenograft model.…”

Section: Discussionmentioning

confidence: 99%

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

Hernando

¹

,

Gelato

²

,

Lesche

³

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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“…HDACs, key enzymes regulating the acetylation status of both histone-and non-histone proteins, are classified into 4 classes: class I (HDAC1, 2,3,8), class IIa (HDAC4, 5, 7, 9) and class IIb (HDAC6,10), class-III (SIRT1-7), and class-IV (HDAC11; ref. 12).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

Amodio

¹

,

Stamato

²

,

Gullà

³

et al. 2016

Molecular Cancer Therapeutics

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Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1364-75. Ó2016 AACR.

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“…A number of epigenetic modifications have been so far linked to cancer, including posttranslational modification of histones, DNA methylation, and the most recently discovered noncoding RNAs, which are currently considered key determinants in human cancer pathogenesis (2). In the last few years, a wealth of studies has shown deep dysregulation of miRNAs in human cancers, including multiple myeloma (3).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

Amodio

¹

,

Stamato

²

,

Gullà

³

et al. 2016

View full text Add to dashboard Cite

Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1-12. Ó2016 AACR.

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The role of epigenetics in the biology of multiple myeloma

Cited by 108 publications

References 101 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

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

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