The H3K27me3 Demethylase dUTX Is a Suppressor of Notch- and Rb-Dependent Tumors in <i>Drosophila</i>

Cancer is traditionally viewed as a primarily genetic disorder. However, it is now increasingly apparent that epigenetic abnormalities play a fundamental role in cancer development. Aberrant expression of histone-modifying enzymes has been implicated in the course of tumor initiation and progression. The discovery of a large number of histone demethylases suggests an important role for dynamic regulation of histone methylation in biological processes. The observation that overexpression, amplification or mutations of several histone demethylases have been found in many types of tumors, raise the possibility of using these enzymes as diagnostic tools as well as pave a way for the discovery of novel therapeutic targets and treatment modalities. Here, we review the current knowledge of the potential role of H3K4, H3K9 and H3K27 histone demethylases in tumorigenesis.Recently, it has become apparent that not only genetic mutations but also epigenetic alterations lead to the activation of oncogenes and the loss of function of tumor-suppressor genes. Since epigenetic abnormalities in DNA methylation patterns as well as histone modifications are potentially reversible in contrast to gene mutations, much effort has been directed toward understanding the mechanism of epigenetic aberration to develop epigenetic therapies. Indeed, inhibitors of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) have been approved for treatment of certain types of cancers. Recently, overexpression, amplification or mutations of several histone demethylases have been linked to many types of tumor, raising the possibility of using these enzymes as diagnostic tools and therapeutic targets. Here, we focus mainly on the potential role of some selected histone lysine demethylases in tumorigenesis.The N-terminal tails of histones are subjected to several types of post-translational modifications, including acetylation, methylation, phosphorylation and ubiquitination. The combination of these modifications determines chromatin structure and transcriptional activation or repression of genes. In contrast to other histone modifications, the importance of histone methylations is highlighted because of their enormously specific dynamics with respect to gene regulation. Histone lysine residues on histone H3 and H4 (H3K4, H3K9, H3K27, H3K36, H3K79 and H4K20) can become mono-, dior trimethylated. These modifications are regulated by two classes of enzymes with opposing activities: histone methyltransferases and histone lysine demethylases. LSD1, also known as AOF2 and KDM1, is the first discovered histone lysine demethylase that belongs to the flavin adenine dinucleotide-dependent enzyme family. 1 Subsequently, another family of histone lysine demethylases structurally different from LSD1 was described, all of which sharing the conserved jumonji C (JmjC) domain (Table 1). H3K4 Demethylases in Cancer LSD1/KDM1ATri-and dimethylated H3K4 (H3K4me3/2) are often found at actively transcribed genes. Although H3K4me3 is highly enriched around transcrip...

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“…In addition to the UTX-pRB pathway connections, UTX was also shown to be a Notch antagonist for cell cycle control in Drosophila. 46 …”

Section: Utx/kdm6amentioning

confidence: 99%

Epigenetic regulation of cancer growth by histone demethylases

Lim

Metzger

Schüle

et al. 2010

Intl Journal of Cancer

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mentioning

confidence: 99%

“…Despite progress in making biochemical assignments, the physiological roles of most 2OG oxygenases predicted by bioinformatic analysis of animal genomes are unknown. For instance, we have identified ∼50 putative 2OG oxygenases in the Drosophila genome, but only a few are characterized (7,8).The function of Fatiga, the single Drosophila homolog of human hypoxia inducible transcription factor (HIF) prolyl-4-hydroxylases (PHDs), has been well studied in the context of oxygen sensing (9). HIF prolyl-hydroxylation plays a central role in the animal hypoxic response via hydroxylation of HIF, a posttranslational modification that signals for HIF-α degradation in a physiologically relevant oxygen-dependent manner (10, 11).…”

mentioning

confidence: 99%

Sudestada1, a Drosophila ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth

Katz

Acevedo

Loenarz

et al. 2014

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

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Genome sequences predict the presence of many 2-oxoglutarate (2OG)-dependent oxygenases of unknown biochemical and biological functions in Drosophila. Ribosomal protein hydroxylation is emerging as an important 2OG oxygenase catalyzed pathway, but its biological functions are unclear. We report investigations on the function of Sudestada1 (Sud1), a Drosophila ribosomal oxygenase. As with its human and yeast homologs, OGFOD1 and Tpa1p, respectively, we identified Sud1 to catalyze prolyl-hydroxylation of the small ribosomal subunit protein RPS23. Like OGFOD1, Sud1 catalyzes a single prolyl-hydroxylation of RPS23 in contrast to yeast Tpa1p, where Pro-64 dihydroxylation is observed. RNAi-mediated Sud1 knockdown hinders normal growth in different Drosophila tissues. Growth impairment originates from both reduction of cell size and diminution of the number of cells and correlates with impaired translation efficiency and activation of the unfolded protein response in the endoplasmic reticulum. This is accompanied by phosphorylation of eIF2α and concomitant formation of stress granules, as well as promotion of autophagy and apoptosis. These observations, together with those on enzyme homologs described in the companion articles, reveal conserved biochemical and biological roles for a widely distributed ribosomal oxygenase.fruit fly | ribosome | dioxygenase | proline | tranlational stress I ron [Fe(II)]-and 2-oxoglutarate (2OG)-dependent oxygenases are a superfamily with diverse biochemical and biological functions. During 2OG oxygenase catalysis, substrate oxidation is coupled to decarboxylation of 2OG, yielding succinate and carbon dioxide (1, 2). Structural studies reveal that the catalytic domain of 2OG oxygenases contains a conserved double-stranded β-helix (DSBH) fold presenting an HXD. . .H facial triad motif that coordinates an Fe(II) cofactor (3, 4). These and other structural features have been used to predict the existence of multiple uncharacterized 2OG oxygenases. In contrast to microorganisms and plants where 2OG oxygenases catalyze a wide variety of oxidative reactions, in animals their biochemical activities appear limited to hydroxylations or demethylations via hydroxylation (1,5,6). Despite progress in making biochemical assignments, the physiological roles of most 2OG oxygenases predicted by bioinformatic analysis of animal genomes are unknown. For instance, we have identified ∼50 putative 2OG oxygenases in the Drosophila genome, but only a few are characterized (7,8).The function of Fatiga, the single Drosophila homolog of human hypoxia inducible transcription factor (HIF) prolyl-4-hydroxylases (PHDs), has been well studied in the context of oxygen sensing (9). HIF prolyl-hydroxylation plays a central role in the animal hypoxic response via hydroxylation of HIF, a posttranslational modification that signals for HIF-α degradation in a physiologically relevant oxygen-dependent manner (10, 11). Given the tractability of these enzymes as targets for pharmacological modulation by 2OG analogs and related co...

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“…The KDM6A and MLL2 gene functioned together in the epigenetic control of transcriptionally active chromatin and were also previously identified, in combination as well as independently, to have significant roles in the regulation of muscle-specific genes during embryogenesis and development. [31][32][33] A broad phenotypic spectrum was also observed between these patients, all three of whom did, however, posses many of the characteristic facial features.…”

Section: The Mll2 Gene Associationmentioning

confidence: 89%

Kabuki syndrome revisited

Bokinni

2012

J Hum Genet

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Kabuki syndrome (KS) is a congenital syndrome with an estimated prevalence of 1 in 32 000. Individuals with the syndrome have multiple malformations, but remain identifiable by the presence of the distinctive craniofacial anomalies associated with the condition. Discovered in 1981 by two independent groups of Japanese scientists, spearheaded by Yoshikazu Kuroki and Norio Niikawa, much ambiguity relating to the syndrome persisted for over 30 years after it was initially discovered, with no definitive conclusions about its etiology having ever been established. Recently, mutations within the MLL2 gene have been identified as potentially implicative. Mutations within the MLL2 gene in KS patients have been promising not only because of their relatively high presence in affected individuals, but also because of pre-existing information in the literature having validated mutant MLL2 genes in KS as a highly significant finding. Although found to be present in the majority of cases, the absence of MLL2 mutations in all patients with the syndrome is suggestive that the condition may still display a degree of genetic heterogeneity, and further still, present with more complex inter genomic interactions than initially proposed.

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The H3K27me3 Demethylase dUTX Is a Suppressor of Notch- and Rb-Dependent Tumors in Drosophila

Cited by 105 publications

References 85 publications

Epigenetic regulation of cancer growth by histone demethylases

Epigenetic regulation of cancer growth by histone demethylases

Sudestada1, a Drosophila ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth

Kabuki syndrome revisited

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