NSD2 Is Recruited through Its PHD Domain to Oncogenic Gene Loci to Drive Multiple Myeloma

Huang, Zheng; Wu, Haiping; Chuai, Shannon; Xu, Fiona; Yuan, Feng; Englund, Nathan; Wang, Zhaofu; Zhang, Hailong; Fang, Ming; Wang, Youzhen; Gu, Justin; Zhang, Man; Yang, Teddy; Zhao, Kehao; Yu, Yanyan; Dai, Jingquan; Yi, Wei; Zhou, Shaolian; Li, Qian; Wu, Jing; Li, Jun; Wu, Xu; Chan, Homan; Lu, Chris X.; Atadja, Peter; Li, En; Wang, Yan; Hu, Min

doi:10.1158/0008-5472.can-13-1000

Cited by 63 publications

(66 citation statements)

References 49 publications

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“…S1A), which might reflect the complexity of possible protein products from the MMSET gene (13). However, each of these cell lines presented high amounts of H3K36me2 combined with low levels of H3K27me3, and the inverse occurred for the cell lines without the t(4;14) translocation, confirming results also reported by others (27). The protein levels of EZH2 and JMJD3 (another H3K27me3-specific demethylase not reported to be altered in multiple myeloma) showed slight differences, which did not correlate with global H3K27me3 levels (Fig.…”

Section: Ezh2 Inhibition Induces Time-dependent Antiproliferative Effsupporting

confidence: 88%

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: Ezh2 Inhibition Induces Time-dependent Antiproliferative Effsupporting

confidence: 88%

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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“…Furthermore, complementation of MMSET knockout cells with wild-type MMSET (rather than catalytic mutants) could restore their tumorigenicity in vivo. 15,18 These data further confirmed that MMSET is an oncogene and that its oncogenic role is dependent on its catalytic activity. Despite the aforementioned data, the exact molecular targets underlying MMSET activity are not well understood.…”

Section: Introductionsupporting

confidence: 61%

MMSET regulates expression of IRF4 in t(4;14) myeloma and its silencing potentiates the effect of bortezomib

Xie

Chooi

et al. 2015

Leukemia

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Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. In t(4;14) MM, the MM SET domain (MMSET) protein is universally overexpressed and has been suggested to have an important tumorigenic role. However, the exact molecular targets underlying MMSET activity are not well understood. Here, we found in t(4;14) MM cells that MMSET knockdown decreases interferon regulatory factor 4 (IRF4) expression, and ectopic MMSET increases IRF4 expression, suggesting that MMSET is an upstream regulator of IRF4. Further analyses indicated an interaction between MMSET and nuclear factor-κB, which both bind to the IRF4 promoter region. A luciferase reporter assay showed that MMSET is an important functional element for the IRF4 promoter. MMSET knockdown induces apoptosis and potentiates the effects of bortezomib in vitro and in vivo. Importantly, we found that bortezomib could reduce expression of MMSET and IRF4. This might partly explain the additive effect of combining MMSET knockdown and bortezomib treatment. These results identify MMSET as a key regulator involved in the regulatory network of transcription factor IRF4, which is critical for MM cell survival, suggesting that the combination of MMSET inhibition and bortezomib is likely to improve patient outcome in MM.

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“…NSD2 knockdown selectively inhibited the proliferation and xenograft growth of ALL lines harboring the E1099K mutation in NSD2, indicating its requirement for NSD2 mutant ALL (Jaffe et al 2013). In addition to the therapeutic targeting of NSD2's catalytic activity, an essential function for the second plant homeodomain (PHD) finger in targeting NSD2 to chromatin provides another potential therapeutic strategy (Huang et al 2013b). Last, the oncogenic potential of NSD3 was first suggested by the observation that it was overexpressed in breast cancer and was later found as a fusion partner of the NUT oncogene in midline carcinoma (Filippakopoulos et al 2010).…”

Section: The Nuclear Receptor-binding Set Domain (Nsd) Family Of H3k3mentioning

confidence: 99%

Epigenetics of hematopoiesis and hematological malignancies

Hu¹,

Shilatifard

2016

Genes Dev.

127

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Hematological malignancies comprise a diverse set of lymphoid and myeloid neoplasms in which normal hematopoiesis has gone awry and together account for ∼10% of all new cancer cases diagnosed in the United States in 2016. Recent intensive genomic sequencing of hematopoietic malignancies has identified recurrent mutations in genes that encode regulators of chromatin structure and function, highlighting the central role that aberrant epigenetic regulation plays in the pathogenesis of these neoplasms. Deciphering the molecular mechanisms for how alterations in epigenetic modifiers, specifically histone and DNA methylases and demethylases, drive hematopoietic cancer could provide new avenues for developing novel targeted epigenetic therapies for treating hematological malignancies. Just as past studies of blood cancers led to pioneering discoveries relevant to other cancers, determining the contribution of epigenetic modifiers in hematologic cancers could also have a broader impact on our understanding of the pathogenesis of solid tumors in which these factors are mutated.

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NSD2 Is Recruited through Its PHD Domain to Oncogenic Gene Loci to Drive Multiple Myeloma

Cited by 63 publications

References 49 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

MMSET regulates expression of IRF4 in t(4;14) myeloma and its silencing potentiates the effect of bortezomib

Epigenetics of hematopoiesis and hematological malignancies

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