Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer

Liu, G; Bollig‐Fischer, Aliccia; Kreike, Bas; Vijver, Marc J. van de; Abrams, Judith; Ethier, Stephen P.; Yang, Zunhua

doi:10.1038/onc.2009.297

Cited by 184 publications

(201 citation statements)

References 45 publications

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“…6,[12][13][14][15] It is noteworthy that LSD1, GASC1/JMJD2C and PKCb 1 are aberrantly upregulated in prostate cancer, suggesting that these enzymes might function together in pathological settings. 7,9,14,16 The underlying mechanism by which overexpression of LSD1 leads or contributes to tumor formation is not fully elucidated, possibly because of its widespread role in biological processes. However, it is possible that specific tumorigenic effects of LSD1 are linked to its capacity to silence tumor suppressor genes as a transcriptional corepressor ( Table 3).…”

Section: Lsd1/kdm1amentioning

confidence: 99%

“…14 Among them, JMJD2C, also known as GASC1 and KDM4C, has already been reported as a gene amplified in various malignancies (Table 1). 16 Depletion of GASC1 from cancer cells, expressing high levels of GASC1, resulted in inhibition of cell growth, 14 whereas overexpression of GASC1 in human nontransformed mammary epithelial cells resulted in phenotypic alterations that are hallmarks of neoplastic transformation, including growth factor-independent proliferation and anchorage-independent growth in soft agar. Introduction of GASC1 gene in normal breast MCF10A cells could increase higher capacity to generate mammospheres, a phenotype of cancer stem cells, suggesting that GASC1 acts as a transforming gene.…”

Section: Gasc1/jmjd2c/kdm4cmentioning

confidence: 99%

“…Analysis of genes altered by overexpression of GASC1 in MCF10A-GASC1 cells revealed NOTCH1 as a target gene of GASC1. 16 Induction of NOTCH signaling promotes self-renewal of normal human mammary stem cells. This may support the finding that the phenotype of cancer stem cell was increased in MCF10A-GASC1 cells.…”

Section: Gasc1/jmjd2c/kdm4cmentioning

confidence: 99%

“…Introduction of GASC1 gene in normal breast MCF10A cells could increase higher capacity to generate mammospheres, a phenotype of cancer stem cells, suggesting that GASC1 acts as a transforming gene. 16 GASC1 can function as a transcriptional activator by removing the euchromatic H3K9me3, which is generally associated with transcriptional repression. Analysis of genes altered by overexpression of GASC1 in MCF10A-GASC1 cells revealed NOTCH1 as a target gene of GASC1.…”

Section: Gasc1/jmjd2c/kdm4cmentioning

confidence: 99%

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Epigenetic regulation of cancer growth by histone demethylases

Lim

Metzger

Schüle

et al. 2010

Intl Journal of Cancer

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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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Section: Lsd1/kdm1amentioning

confidence: 99%

Section: Gasc1/jmjd2c/kdm4cmentioning

confidence: 99%

Section: Gasc1/jmjd2c/kdm4cmentioning

confidence: 99%

Section: Gasc1/jmjd2c/kdm4cmentioning

confidence: 99%

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Epigenetic regulation of cancer growth by histone demethylases

Lim

Metzger

Schüle

et al. 2010

Intl Journal of Cancer

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“…The Jumonji-C histone demethylase family member, Jumonji domain-containing 2C (JMJD2C), removes trimethyl groups from lysines 9 and 36 of histone H3 by an oxidative reaction that requires iron and α-ketoglutarate as cofactors (6). Knockdown of JMJD2C decreased proliferation of tumor cells, whereas its expression in mammary epithelial cells induced a transformed phenotype (6,7). JMJD2C is also an important mediator of embryonic stem-cell self-renewal via positive regulation of the key transcription factor Nanog (8).…”

mentioning

confidence: 99%

Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation

Burton

Azevedo

Andreassi

et al. 2013

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

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Epigenetic modifications of chromatin represent a fundamental mechanism by which eukaryotic cells adapt their transcriptional response to developmental and environmental cues. Although an increasing number of molecules have been linked to epigenetic changes, the intracellular pathways that lead to their activation/ repression have just begun to be characterized. Here, we demonstrate that inositol hexakisphosphate kinase 1 (IP 6 K1), the enzyme responsible for the synthesis of the high-energy inositol pyrophosphates (IP 7 ), is associated with chromatin and interacts with Jumonji domain containing 2C (JMJD2C), a recently identified histone lysine demethylase. Reducing IP 6 K1 levels by RNAi or using mouse embryonic fibroblasts derived from ip6k1 −/− knockout mice results in a decreased IP 7 concentration that epigenetically translates to reduced levels of trimethyl-histone H3 lysine 9 (H3K9me3) and increased levels of acetyl-H3K9. Conversely, expression of IP 6 K1 induces JMJD2C dissociation from chromatin and increases H3K9me3 levels, which depend on IP 6 K1 catalytic activity. Importantly, these effects lead to changes in JMJD2C-target gene transcription. Our findings demonstrate that inositol pyrophosphate signaling influences nuclear functions by regulating histone modifications.inositides | phosphorylation | metabolism E pigenetic modifications of histones are emerging as a central mechanism that controls nuclear functions, transducing changes in cell physiology to transcriptional reprogramming (1). Histones are subjected to numerous reversible posttranslational modifications, including acetylation, phosphorylation, methylation, ubiquitylation, ADP ribosylation, and sumoylation (2). Histone methylation has been associated with transcriptional control, mRNA splicing, DNA repair, and replication (3). Recently two families of histone demethylase enzymes have been identified in mammalian cells, lysine-specific demethylase 1 and the Jumonji-C domain-containing proteins (4, 5). The Jumonji-C histone demethylase family member, Jumonji domain-containing 2C (JMJD2C), removes trimethyl groups from lysines 9 and 36 of histone H3 by an oxidative reaction that requires iron and α-ketoglutarate as cofactors (6). Knockdown of JMJD2C decreased proliferation of tumor cells, whereas its expression in mammary epithelial cells induced a transformed phenotype (6, 7). JMJD2C is also an important mediator of embryonic stem-cell self-renewal via positive regulation of the key transcription factor Nanog (8).Inositol pyrophosphates, including diphosphoinositol pentakisphosphate or PP-IP 5 (IP 7 ), belong to a specific class of inositol polyphosphates that undergo very rapid turnover (9, 10). They possess highly energetic pyrophosphate moieties that participate in phosphotransfer reactions (11,12). Inositol pyrophosphates regulate many diverse cellular events (for review, see refs. 13-15) and this is likely to reflect their ability to control a very basic cellular function. In fact, recent discoveries indicate inositol pyrophosphate...

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Genotranscriptomic meta‐analysis of the CHD family chromatin remodelers in human cancers – initial evidence of an oncogenic role for CHD7

et al. 2017

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Chromodomain helicase DNA binding proteins (CHDs) are characterized by N‐terminal tandem chromodomains and a central adenosine triphosphate‐dependent helicase domain. CHDs govern the cellular machinery's access to DNA, thereby playing critical roles in various cellular processes including transcription, proliferation, and DNA damage repair. Accumulating evidence demonstrates that mutation and dysregulation of CHDs are implicated in the pathogenesis of developmental disorders and cancer. However, we know little about genomic and transcriptomic alterations and the clinical significance of most CHDs in human cancer. We used TCGA and METABRIC datasets to perform integrated genomic and transcriptomic analyses of nine CHD genes in more than 10 000 primary cancer specimens from 32 tumor types, focusing on breast cancers. We identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival. We found that CHD7 was the most commonly gained/amplified and mutated, whereas CHD3 was the most deleted across the majority of tumor types, including breast cancer. Overexpression of CHD7 was more prevalent in aggressive subtypes of breast cancer and was significantly correlated with high tumor grade and poor prognosis. CHD7 is required to maintain open, accessible chromatin, thus providing fine‐tuning of transcriptional regulation of certain classes of genes. We found that CHD7 expression was positively correlated with a small subset of classical oncogenes, notably NRAS, in breast cancer. Knockdown of CHD7 inhibits cell proliferation and decreases gene expression of several CHD7 targets, including NRAS, in breast cancer cell lines. Thus, our results demonstrate the oncogenic potential of CHD7 and its association with poor prognostic parameters in human cancer.

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Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer

Cited by 184 publications

References 45 publications

Epigenetic regulation of cancer growth by histone demethylases

Epigenetic regulation of cancer growth by histone demethylases

Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation

Genotranscriptomic meta‐analysis of the CHD family chromatin remodelers in human cancers – initial evidence of an oncogenic role for CHD7

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