Oncometabolite Tinkers with Genome Folding, Boosting Oncogene Expression

Ing-Simmons, Elizabeth; Merkenschlager, Matthias

doi:10.1016/j.molmed.2016.01.008

Cited by 3 publications

(4 citation statements)

References 10 publications

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“…Nothing, however, is known about its function in the brain or in relation to substance use disorders. In addition, this mark is usually studied in the context of enhancers (33–35) and super-enhancers (36–38), while its functional role in intragenic regions remains elusive. Even less is known about H3K23ac (39, 40) for which a group difference was noted for heroin, but the levels did not relate to drug history or acute use as they did for H3K27ac.…”

Section: Discussionmentioning

confidence: 99%

Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target

Egervári

Landry

Callens

et al. 2017

Biological Psychiatry

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Background Opiate abuse and overdose reached epidemic levels in the USA. However, despite significant advances in animal and in vitro models, little knowledge has been directly accrued regarding the neurobiology of the opiate-addicted human brain. Methods We used post-mortem human brain specimens from a homogeneous European Caucasian population of heroin users for transcriptional and epigenetic profiling as well as direct assessment of chromatin accessibility in the striatum, a brain region central to reward and emotion. A rat heroin self-administration model was used to obtain translational molecular and behavioral insights. Results Our transcriptome approach revealed marked impairments related to glutamatergic neurotransmission and chromatin remodeling in the human striatum. A series of biochemical experiments tracked the specific location of the epigenetic disturbances to hyperacetylation of lysine 27 (H3K27ac) of histone H3, showing dynamic correlations with heroin use history and acute opiate toxicology. Targeted investigation of GRIA1, a glutamatergic gene implicated in drug-seeking behavior, verified the increased enrichment of H3K27ac at discrete loci, accompanied by enhanced chromatin accessibility at hyperacetylated regions in the gene body. Analogous epigenetic impairments were detected in the striatum of heroin self-administering rats. Using this translational model, we showed that bromodomain inhibitor JQ1, which blocks the functional read-out of acetylated lysines, reduced heroin self-administration and cue-induced drug-seeking behavior. Conclusions Overall, our data suggest that heroin-related histone H3 hyperacetylation contributes to glutamatergic transcriptional changes that underlie addiction behavior and identify JQ1 as a promising candidate for targeted clinical interventions in heroin use disorder.

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Section: Discussionmentioning

confidence: 99%

Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target

Egervári

Landry

Callens

et al. 2017

Biological Psychiatry

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“…The AhR pathway can cross talk with other major signaling pathways that might be modulated by oncometabolites that are critical in cancer progression 21 – 23 . We found elevated oncometabolite levels including 2-hydroxyglutarate (2-HG), α-ketoglutarate (α-KG), citrate, fumarate, malate, and succinate in A549-IR and HK1-IR cell sublines compared to P lines (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The AhR pathway can cross talk with other major signaling pathways that might be modulated by oncometabolites that are critical in cancer progression 21 – 23 . Diverse metabolites serve as cofactors or substrates for enzymes that are involved in the deposition or exchange of epigenetic marks, driving a metabolite-driven pathway of gene regulation as well as distinct cancer tissue types 24 , 57 – 59 .…”

Section: Discussionmentioning

confidence: 99%

Activation of AhR with nuclear IKKα regulates cancer stem-like properties in the occurrence of radioresistance

et al. 2018

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Most cancer patients receive radiotherapy in the course of their disease and the occurrence of radioresistance is associated with poor prognosis. The molecular pathways that drive enhanced tumorigenic potential during the development of radioresistance are poorly understood. Here, we demonstrate that aryl hydrocarbon receptor (AhR) plays a vital role in the maintenance of cancer stem-like properties. AhR promotes the cancer stem-like phenotype and drives metastasis by directly targeting the promoters of ‘stemness’ genes, such as the ATP-binding cassette sub-family G member 2 (ABCG2) gene. Moreover, the radioresistant sublines display high levels of oncometabolites including α-ketoglutarate, and treatment of cancer cells with α-ketoglutarate enhances their stem-like properties in an AhR activation-dependent manner. IKKα directly activates stemness-related genes through an interaction with AhR as a bone fide chromatin modifier. Thus, AhR is functionally linked with cancer stem-like properties, and it drives tumorigenesis in the occurrence of radioresistance.

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“…Its mutants (i.e., SNPs rs7864322, rs12352658, rs7847449, and rs10759944) interact with a promoter shared by FOXE1 and PTCSC2 and act as enhancers [ 97 ]. Gliomas also display SNP-mediated interactions in which the oncogene PDGFRA is changed by CTCF-related chromosome folding [ 98 ]. Other interactions among enhancers, SNP rs73001406, and the DDX6 gene promoter affect cancer risk [ 99 ].…”

Section: Roles Of Chromosomal Conformations In Cancermentioning

confidence: 99%

Novel insights into chromosomal conformations in cancer

Jia

Chai

et al. 2017

Mol Cancer

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Exploring gene function is critical for understanding the complexity of life. DNA sequences and the three-dimensional organization of chromatin (chromosomal interactions) are considered enigmatic factors underlying gene function, and interactions between two distant fragments can regulate transactivation activity via mediator proteins. Thus, a series of chromosome conformation capture techniques have been developed, including chromosome conformation capture (3C), circular chromosome conformation capture (4C), chromosome conformation capture carbon copy (5C), and high-resolution chromosome conformation capture (Hi-C). The application of these techniques has expanded to various fields, but cancer remains one of the major topics. Interactions mediated by proteins or long noncoding RNAs (lncRNAs) are typically found using 4C-sequencing and chromatin interaction analysis by paired-end tag sequencing (ChIA-PET). Currently, Hi-C is used to identify chromatin loops between cancer risk-associated single-nucleotide polymorphisms (SNPs) found by genome-wide association studies (GWAS) and their target genes. Chromosomal conformations are responsible for altered gene regulation through several typical mechanisms and contribute to the biological behavior and malignancy of different tumors, particularly prostate cancer, breast cancer and hematologic neoplasms. Moreover, different subtypes may exhibit different 3D-chromosomal conformations. Thus, C-tech can be used to help diagnose cancer subtypes and alleviate cancer progression by destroying specific chromosomal conformations. Here, we review the fundamentals and improvements in chromosome conformation capture techniques and their clinical applications in cancer to provide insight for future research.

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Oncometabolite Tinkers with Genome Folding, Boosting Oncogene Expression

Cited by 3 publications

References 10 publications

Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target

Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target

Activation of AhR with nuclear IKKα regulates cancer stem-like properties in the occurrence of radioresistance

Novel insights into chromosomal conformations in cancer

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