Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers

Chi, Ping; Allis, C. David; Wang, Gang Greg

doi:10.1038/nrc2876

Cited by 991 publications

(863 citation statements)

References 122 publications

(304 reference statements)

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“…Mutation or misregulation of PMTs is linked to many diseases, especially cancer, and there is strong interest in this family of proteins as potential drug targets [1][2][3] . Targeting the common S-adenosylmethionine (SAM) cofactor-binding site of PMTs is an attractive strategy for this family, analogous to targeting the ATP-binding site of protein kinases 4,5 .…”

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confidence: 99%

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

et al. 2012

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Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethioninecompetitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.

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Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

et al. 2012

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“…Covalent modifications of these proteins play critical roles in regulating gene expression (13). Genes encoding these proteins are present in multiple copies in the genome in two clusters (chr1p and chr6p), permitting high expression in S-phase to allow assembly with newly replicated DNA.…”

Section: Resultsmentioning

confidence: 99%

Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition

Zhao

Bellone

Lopez

et al. 2016

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

194

175

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Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC. Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial-mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms.uterine carcinosarcoma | ovarian carcinosarcoma | exome sequencing C arcinosarcomas (CSs) of the female genital tract, also known as mixed malignant Müllerian tumors, are rare but highly aggressive tumors characterized by a biphasic histology. These cancers most commonly arise in the uterus, followed by the ovaries, fallopian tubes, and vagina (1-3). The diagnosis of CS requires the presence of both sarcomatous and carcinomatous components. Although the pathogenesis of CSs remains under debate, an increasing body of evidence supports the origin of both elements from a common epithelial cell that undergoes sarcomatous dedifferentiation, rather than two independent progenitors (2-5).The overall 5-y survival is only 30 ± 9% for all stages, and the recurrence rate after surgery is extremely high (50-80%) (3-5). The uncertain origin and poor prognosis of uterine and ovarian CSs motivate determination of the molecular basis of CS aggressive behavior in the hope of developing novel and effective treatment modalities. ResultsThe Genetic Landscape of CS. A total of 68 patients with stage I-IV uterine (n = 44) and ovarian (n = 24) CSs were studied. Their clinical and histological features are presented in SI Appendix, Table S1. Upon surgical removal of tumors, primary cell lines were prepared (five tumors) or tumors were frozen (63 tumors). Among t...

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“…Each regulatory point in the control of gene expression (which includes chromatin structure, splicing and polyadenylation of mRNA precursors, translation, and mRNA and protein stability) is subject to profound alterations during the development of most, if not all, cancers (Venables 2006;Mayr and Bartel 2009;Chi et al 2010;Silvera et al 2010). Of all of these points in the gene expression pathway, none provides the potential for more diverse outcomes than alternative splicing (AS).…”

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Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

David

Manley²

2010

Genes Dev.

727

667

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Alternative splicing of mRNA precursors is a nearly ubiquitous and extremely flexible point of gene control in humans. It provides cells with the opportunity to create protein isoforms of differing, even opposing, functions from a single gene. Cancer cells often take advantage of this flexibility to produce proteins that promote growth and survival. Many of the isoforms produced in this manner are developmentally regulated and are preferentially re-expressed in tumors. Emerging insights into this process indicate that pathways that are frequently deregulated in cancer often play important roles in promoting aberrant splicing, which in turn contributes to all aspects of tumor biology.

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Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers

Cited by 991 publications

References 122 publications

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

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