NSD3–NUT Fusion Oncoprotein in NUT Midline Carcinoma: Implications for a Novel Oncogenic Mechanism

French, Christopher A.; Rahman, Shaila; Walsh, Erica M.; Kühnle, Simone; Grayson, Adlai R.; Lemieux, Madeleine E.; Grunfeld, Noam; Rubin, Brian P.; Antonescu, Cristina R.; Zhang, Songlin; Venkatramani, Rajkumar; Cin, Paola Dal; Howley, Peter M.

doi:10.1158/2159-8290.cd-14-0014

Cited by 209 publications

(241 citation statements)

References 57 publications

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“…Approximately two‐thirds of NMC cases harbor a BRD4–NUTM1 fusion gene, which has been functionally validated as an oncogenic event 39, 40. In the other one‐third of cases, several fusion partners of NUTM1 have been reported in the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman) and recent papers, such as ACIN1, 41, 42, 43 BCOR1, 44 BRD3, 40 BRD9, 41 BPTF, 45 CIC, 46 CUX1, 42 IKZF1, 42, 47 MXD1, 44 NSD3, 48 SLC12A6, 42 ZNF532, 49 and ZNF618. 42 Although MXD1–NUTM1 fusion has been reported in gastric sarcoma, MXD4 has not been previously reported as a fusion partner of NUTM1.…”

Section: Discussionmentioning

confidence: 99%

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Tamura

Nakaoka

Yoshihara

et al. 2018

Genes Chromosomes & Cancer

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Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in‐frame fusion transcripts: MXD4–NUTM1 and ARL6–POT1. Most NUTM1 exons were retained in the MXD4–NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

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Section: Discussionmentioning

confidence: 99%

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Tamura

Nakaoka

Yoshihara

et al. 2018

Genes Chromosomes & Cancer

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“…Interestingly, in addition to the association of BRD4-NUT and ZNF532 proteins in 797TRex patient cells, we found that the ZNF532 locus is a binding target for BRD4-NUT. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis using anti-NUT antibodies revealed strong enrichment over or adjacent to the ZNF532 locus in a variety of NMC cells, including TC-797, 797TRex, 10-15 (16), and PER-403 (17), all of which harbor a BRD4-NUT fusion, and also 10326 cells, which carry a BRD3-NUT translocation (7) (Fig. 2C).…”

Section: Ep300mentioning

confidence: 99%

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

Alekseyenko

Walsh

Zee

et al. 2017

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

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To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma (NMC), we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared with wild-type BRD4. Using cross-linking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 associated with BRD4-NUT in NMC patient cells but not detectable in 293T cells. EP300 and ZNF532 are both implicated in feed-forward regulatory loops leading to propagation of the oncogenic chromatin complex in BRD4-NUT patient cells. Adding key functional significance to our biochemical findings, we independently discovered a ZNF532-NUT translocation fusion in a newly diagnosed NMC patient. ChIP sequencing of the major players NUT, ZNF532, BRD4, EP300, and H3K27ac revealed the formation of ZNF532-NUT-associated hyperacetylated megadomains, distinctly localized but otherwise analogous to those found in BRD4-NUT patient cells. Our results support a model in which NMC is dependent on ectopic NUT-mediated interactions between EP300 and components of BRD4 regulatory complexes, leading to a cascade of misregulation.BioTAP-XL | hyperacetylation | ZNF532-NUT | topological domains | BRD4

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“…For example, recent studies have shown that NSD3 engages in a rich repertoire of PPIs with other chromatin readers and remodelers. In a subset of NUT midline carcinoma (NMC) cases, an NSD3-NUT fusion protein, which lacks the NSD3 SET domain, blocks differentiation [148]. The NSD3 N-terminus in the fusion protein interacts with the bromodomaincontaining protein BRD4 to drive oncogenesis, and NSD3-NUT NMC cells are sensitive to the bromodomain inhibitor JQ1.…”

Section: Alternative Druggable Regions Of H3k36 Kmtase Proteinsmentioning

confidence: 99%

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

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NSD3–NUT Fusion Oncoprotein in NUT Midline Carcinoma: Implications for a Novel Oncogenic Mechanism

Cited by 209 publications

References 57 publications

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

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