Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies

Nakagawa, Makoto; Kitabayashi, Issay

doi:10.1111/cas.13655

Cited by 37 publications

(30 citation statements)

References 86 publications

(114 reference statements)

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“…33 In this study, neither abnormal clinical signs nor significant body weight loss was observed in mice throughout longterm continuous administration of OR-S1 for 150 days; therefore, long-term continuous administration would be a clinically feasible regimen. 34,51 This favorable safety profile has enabled us to move forward to clinical trials as the only clinically applicable EZH1/2 inhibitor; 29 subsequently evaluating the effect of OR-S1 against MM patients would be encouraged as a novel therapeutic option for relapsed MM.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, selective EZH2 inhibitors have been developed and some of them are currently being investigated in clinical trials against various malignant tumors, including MM. [26][27][28][29] Furthermore, upregulation of EZH2 in SP cells has been reported and this suggests that EZH2 has an important role for stem cell maintenance in MM. 10 However, it remains unclear whether EZH1, the other catalytic subunit of PRC2, is important to maintain the stemness of MM cells, although EZH1 only partially compensates for loss of EZH2 in stem cell maintenance.…”

Section: Introductionmentioning

confidence: 96%

“…These results suggest that overexpression of EZH2 is responsible for tumor progression and that EZH2 is a potential therapeutic target in MM. Indeed, selective EZH2 inhibitors have been developed and some of them are currently being investigated in clinical trials against various malignant tumors, including MM . Furthermore, upregulation of EZH2 in SP cells has been reported and this suggests that EZH2 has an important role for stem cell maintenance in MM …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma

Nakagawa

Fujita²,

Katsumoto³

et al. 2018

Cancer Science

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Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug‐resistant myeloma stem cells. Side population (SP) cells show cancer stem cell‐like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non‐SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR‐S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient‐derived xenograft model. Moreover, long‐term continuous dosing of OR‐S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR‐S1, leading to significant advances in the treatment of MM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma

Nakagawa

Fujita²,

Katsumoto³

et al. 2018

Cancer Science

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“…In addition, PVT1 was reported to recruit EZH2 [99] to LATS2 [100], CDKN2B and CDKN2A [101] promoters, in order to repress their transcription, suggesting a MYC-independent activity. Although this evidence was obtained in solid tumor models, the involved genes, and in particular the epigenetic regulator EZH2 are well known also in hematological malignancies [102], thus deserving further investigation.…”

Section: Pvt1 and Circpvt1: Myc Partners In Crime And Beyondmentioning

confidence: 95%

Linear and circular PVT1 in hematological malignancies and immune response: two faces of the same coin

et al. 2020

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Non coding RNAs (ncRNAs) have emerged as regulators of human carcinogenesis by affecting the expression of key tumor suppressor genes and oncogenes. They are divided into short and long ncRNAs, according to their length. Circular RNAs (circRNAs) are included in the second group and were recently discovered as being originated by back-splicing, joining either single or multiple exons, or exons with retained introns. The human Plasmacytoma Variant Translocation 1 (PVT1) gene maps on the long arm of chromosome 8 (8q24) and encodes for 52 ncRNAs variants, including 26 linear and 26 circular isoforms, and 6 microRNAs. PVT1 genomic locus is 54 Kb downstream to MYC and several interactions have been described among these two genes, including a feedback regulatory mechanism. MYC-independent functions of PVT1/circPVT1 have been also reported, especially in the regulation of immune responses. We here review and discuss the role of both PVT1 and circPVT1 in the hematopoietic system. No information is currently available concerning their transforming ability in hematopoietic cells. However, present literature supports their cooperation with a more aggressive and/or undifferentiated cell phenotype, thus contributing to cancer progression. PVT1/circPVT1 upregulation through genomic amplification or rearrangements and/or increased transcription, provides a proliferative advantage to malignant cells in acute myeloid leukemia, acute promyelocytic leukemia, Burkitt lymphoma, multiple myeloma (linear PVT1) and acute lymphoblastic leukemia (circPVT1). In addition, PVT1 and circPVT1 regulate immune responses: the overexpression of the linear form in myeloid derived suppressor cells induced immune tolerance in preclinical tumor models and circPVT1 showed immunosuppressive properties in myeloid and lymphoid cell subsets. Overall, these recent data on PVT1 and circPVT1 functions in hematological malignancies and immune responses reflect two faces of the same coin: involvement in cancer progression by promoting a more aggressive phenotype of malignant cells and negative regulation of the immune system as a novel potential therapy-resistance mechanism.

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“…Because of the bimodal pathogenic functions of EZH2 as an oncogene and a tumor suppressor gene, pharmacological inhibition of EZH2 and both EZH1 and EZH2 has being tested extensively in pre-clinical and clinical studies in solid tumors, B-cell lymphoma, and AML [45]. An Ezh2 insufficiency aberrantly activates expression of certain oncogenes because of reduced levels of H3K27me3, but Ezh1-PRC2 partly compensates for Ezh2 loss in the maintenance of transcriptional repression of Ezh2 target genes [46].…”

Section: Targeting Therapy Against Ezh1 and Ezh2 In Myeloid Malignanciesmentioning

confidence: 99%

Deregulated Polycomb functions in myeloproliferative neoplasms

2019

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Polycomb proteins function in the maintenance of gene silencing via post-translational modifications of histones and chromatin compaction. Genetic and biochemical studies have revealed that the repressive function of Polycomb repressive complexes (PRCs) in transcription is counteracted by the activating function of Trithorax-group complexes; this balance fine-tunes the expression of genes critical for development and tissue homeostasis. The function of PRCs is frequently dysregulated in various cancer cells due to altered expression or recurrent somatic mutations in PRC genes. The tumor suppressive functions of EZH2-containing PRC2 and a PRC2-related protein ASXL1 have been investigated extensively in the pathogenesis of hematological malignancies, including myeloproliferative neoplasms (MPN). BCOR, a component of non-canonical PRC1, suppresses various hematological malignancies including MPN. In this review, we focus on recent findings on the role of PRCs in the pathogenesis of MPN and the therapeutic impact of targeting the pathological functions of PRCs in MPN.

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Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies

Cited by 37 publications

References 86 publications

Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma

Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma

Linear and circular PVT1 in hematological malignancies and immune response: two faces of the same coin

Deregulated Polycomb functions in myeloproliferative neoplasms

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