Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

Kikuchi, Jiro; Koyama, Daisuke; Wada, Taeko; Izumi, Tohru; Hofgaard, Peter O.; Bogen, Bjarne; Furukawa, Yusuke

doi:10.1172/jci80325

Cited by 82 publications

(82 citation statements)

References 48 publications

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“…In contrast, HIF1-α was able to induce EZH2 mRNA expression, as is consistent with a previous report identifying hypoxic response element in EZH2 promoter (25). Of interest, a recent study has reported that PRC2/H3K27me3 inactivation induces HIF1A mRNA expression in multiple myeloma (54). Thus, it is possible that the high HIF1A mRNA expression in TNBC is related to the loss of PRC2 activity, thereby conferring a reciprocal negative feedback loop between HIF1-α and PRC2 in TNBC.…”

Section: Discussionsupporting

confidence: 92%

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Mahara

Lee

Feng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Despite the established oncogenic function of Polycomb repressive complex 2 (PRC2) in human cancers, its role as a tumor suppressor is also evident; however, the mechanism underlying the regulation of the paradoxical functions of PRC2 in tumorigenesis is poorly understood. Here we show that hypoxia-inducible factor 1, α-subunit (HIFI-α) is a crucial modulator of PRC2 and enhancer of zeste 2 (EZH2) function in breast cancer. Interrogating the genomic expression of breast cancer indicates high HIF1A activity correlated with high EZH2 expression but low PRC2 activity in triple-negative breast cancer compared with other cancer subtypes. In the absence of HIFIA activation, PRC2 represses the expression of matrix metalloproteinase genes (MMPs) and invasion, whereas a discrete Ezh2 complexed with Forkhead box M1 (FoxM1) acts to promote the expression of MMPs. HIF1-α induction upon hypoxia results in PRC2 inactivation by selective suppression of the expression of suppressor of zeste 12 protein homolog (SUZ12) and embryonic ectoderm development (EED), leading to a functional switch toward Ezh2/FoxM1-dependent induction of the expression of MMPs and invasion. Our study suggests a tumor-suppressive function of PRC2, which is restricted by HIF1-α, and an oncogenic function of Ezh2, which cooperates with FoxM1 to promote invasion in triple-negative breast cancer.

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Section: Discussionsupporting

confidence: 92%

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Mahara

Lee

Feng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The progression of MM involves primary cytogenetic abnormalities (cyclin D, fibroblast growth factor receptor 3, histone-lysine N-methyltransferase, or musculoaponeurotic fibrosarcoma) in myeloma-initiating cells. The oncogenic growth of MM cells is hypothesized to be supported by intracellular oncogenic events and tumor microenvironment components, such as bone marrow stromal cells (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Anthelmintic pyrvinium pamoate blocks Wnt/β-catenin and induces apoptosis in multiple myeloma cells

Zhu

et al. 2018

Oncol Lett

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Abstract. Multiple myeloma (MM) is a malignancy of the bone marrow. The median survival time of patients with MM is only 5 years, with patients frequently experiencing relapse. Currently, there is no effective therapy for recurrent MM. The results of the present study indicated that pyrvinium pamoate (PP), a US Food and Drug Administration-approved oral anthelmintic drug, exhibited potent antitumor activity in MM cells in vitro. It is demonstrated that PP inhibited MM cell proliferation and mediated apoptosis. Notably, PP markedly promoted the degradation of β-catenin and abrogated its phosphorylation. PP triggered apoptosis in MM cells by inducing the release of cytochrome c and downregulating the expression of myeloid leukemia cell differentiation protein.In addition, PP effectively induced cell death in primary MM cells. In conclusion, PP may be a promising agent for the clinical treatment of MM.

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“…They decrease levels of H3K27me, and reactivate transcription of PRC2/H3K27me repressed genes involved in cell cycle regulation and differentiation (76–79). While these studies have shown promising results, other studies have noted enhanced drug resistance with EZH2i (80). EZH2 oncogenic activity has also been attributed to non-enzymatic functions (81), and therefore inhibitors of its catalytic site may not fully suppress its tumor promoting activity.…”

Section: Drugs Targeting Histone Methylationmentioning

confidence: 99%

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

Dupéré-Richér

Licht

2017

Current Opinion in Hematology

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Purpose of review Next generation sequencing and large scale analysis of patient specimens has created a more complete picture of Multiple Myeloma (MM) revealing that epigenetic deregulation is a prominent factor in MM pathogenesis. Recent findings Over half of MM patients have mutations in genes encoding epigenetic modifier enzymes. The DNA methylation profile of MM is related to the stage of the disease and certain classes of mutations in epigenetic modifiers are more prevalent upon disease relapse, suggesting a role in disease progression. Many small molecules targeting regulators of epigenetic machinery have been developed and clinical trials are underway for some of these in MM. Summary Recent findings suggest that epigenetic targeting drugs could be an important strategy to cure MM. Combining these agents along with other strategies to affect the MM cell such as IMIDs and proteasome inhibitors may enhance efficacy of combination regimens in MM.

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Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

Cited by 82 publications

References 48 publications

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Anthelmintic pyrvinium pamoate blocks Wnt/β-catenin and induces apoptosis in multiple myeloma cells

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

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