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The Keap1-Nrf2-Bach1 signaling mediates UBR7 negative regulation of HK2 to inhibit glycolysis and HCC tumorigenesis [RNA-seq]

ABSTRACT: We found that Keap1-Nrf2 signaling pathway mediates UBR7 to regulate HK2 expression through the modification of histone H2BK120 monoubiquitination, thereby inhibiting glycolysis and HCC tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE173501 | GEO | 2022/12/09

REPOSITORIES: GEO

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The Keap1-Nrf2-Bach1 signaling mediates UBR7 negative regulation of HK2 to inhibit glycolysis and HCC tumorigenesis

Project description:We found that Keap1-Nrf2 signaling pathway mediates UBR7 to regulate HK2 expression through the modification of histone H2BK120 monoubiquitination, thereby inhibiting glycolysis and HCC tumorigenesis.

2022-12-09 | GSE173454 | GEO

UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis.

Project description:BackgroundGlycolysis metabolism is an attractive target for cancer therapy. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options. The ubiquitin-proteasome system facilitates the turnover of most intracellular proteins with E3 ligase conferring the target selection and specificity. Ubiquitin protein ligase E3 component N-recognin 7 (UBR7), among the least studied E3 ligases, recognizes its substrate through a plant homeodomain (PHD) finger. Here, we bring into focus on its suppressive role in glycolysis and HCC tumorigenesis, dependent on its E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine 120 (H2BK120ub).MethodsIn this study, we carried out high-throughput RNAi screening to identify epigenetic candidates in regulating lactic acid and investigated its possible roles in HCC progression.ResultsUBR7 loss promotes HCC tumorigenesis both in vitro and in vivo. UBR7 inhibits glycolysis by indirectly suppressing HK2 expression, a downstream target of Nrf2/Bach1 axis. Mechanically, UBR7 regulates H2BK120ub to bind to Keap1 promoter through H2BK120ub monoubiquitination, thereby modulating Keap1 expression and downstream Nrf2/Bach1/HK2 signaling. Pharmaceutical and genetic inhibition of glycolytic enzymes attenuate the promoting effect of UBR7 deficiency on tumor growth. In addition, methyltransferase ALKBH5, downregulated in HCC, regulated UBR7 expression in an m6A-dependent manner.ConclusionsThese results collectively establish UBR7 as a critical negative regulator of aerobic glycolysis and HCC tumorigenesis through regulation of the Keap1/Nrf2/Bach1/HK2 axis, providing a potential clinical and therapeutic target for the HCC treatment.

| S-EPMC9686014 | biostudies-literature

The Keap1-Nrf2-Bach1 signaling mediates UBR7 negative regulation of HK2 to inhibit glycolysis and HCC tumorigenesis

Project description:The Keap1-Nrf2-Bach1 signaling mediates UBR7 negative regulation of HK2 to inhibit glycolysis and HCC tumorigenesis

| PRJNA725561 | ENA

The Keap1-Nrf2-Bach1 signaling mediates UBR7 negative regulation of HK2 to inhibit glycolysis and HCC tumorigenesis [RNA-seq]

Project description:The Keap1-Nrf2-Bach1 signaling mediates UBR7 negative regulation of HK2 to inhibit glycolysis and HCC tumorigenesis [RNA-seq]

| PRJNA725845 | ENA

UBR7 is a novel E3 ubiquitin ligase for H2BK120 and acts as a tumor-suppressor in breast cancer [RNA-Seq]

Project description:Plant Homeo Domain (PHD) is a versatile chromatin reader/effector module which recognizes methylated, acetylated or unmodified histone substrates and regulates cellular gene expression programs. Although PHD domains shows selective epigenetic recognition of methylated, acetylated and unmodified histone substrates, there has been no previous report on its catalytic function regulating malignant transformation of cells. Here we report that PHD finger of UBR7 (Ubiquitin Protein Ligase E3 Component N-Recognin 7 (Putative)), in isolation or in context of full length protein, harbors E3 ubiquitin ligase activity towards monoubiquitination of histone H2B at lysine 120 . Knockdown of UBR7 in MCF10a and breast cancer cells decreased H2BK120ub both at the global levels and on specific genes. Conversely, overexpression of wild type, but not catalytic mutant, rescued H2BK120ub levels. Low UBR7 expression was associated with basal-like and triple negative breast cancers as well as showed poor expression in metastatic tumors. Consistently, UBR7 loss resulted in invasion properties, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 reduced cell growth, invasion and tumor growth in mouse fat pad. Mechanistically, UBR7 reduced H2BK120ub gene body of cell-adhesion related genes as well as gene expression including on CDH4 gene. Importantly, rebuilding CDH4 levels rescued invasion phenotypes seen in UBR7-low cells. Collectively, our results establish that UBR7 PHD has novel H2B ubiquitin ligase activity and it suppresses tumor growth in basal-like breast cancers.

2019-02-08 | GSE93758 | GEO

UBR7 is a novel E3 ubiquitin ligase for H2BK120 and acts as a tumor-suppressor in breast cancer [ChIP-Seq]

2019-02-08 | GSE93757 | GEO

UBR7 Acts as a Chaperone for Post-Nucleosomal Histone H3

Project description:Histone chaperones modulate the stability of histones beginning from histone synthesis, through incorporation into DNA, and during recycling during transcription and replication. Following histone removal from DNA, chaperones regulate histone storage and degradation. Here we characterize UBR7 as a histone H3.1 chaperone that modulates the supply of pre-existing post-nucleosomal histone complexes. UBR7 is a largely nuclear soluble protein. We demonstrate that UBR7 binds to post-nucleosomal H3K4me3 and H3K9me3 histones via its UBR box and PHD. UBR7 binds to the non-nucleosomal histone chaperone NASP. The pool of NASP-bound post-nucleosomal histones accumulate and chromatin is depleted of H3K4me3 nucleosomes in the absence of UBR7. We propose that the interaction of UBR7, NASP, and histones opposes the histone storage functions of NASP as UBR7 promotes reincorporation of post-nucleosomal H3 complexes.

2021-12-02 | GSE183730 | GEO

Keap1

Project description:Drosophila melanogaster Keap1, Keap1, is differentially expressed in 12 experiment(s);

| FBgn0038475 | ExpressionAtlas

Keap1

Project description:Drosophila melanogaster Keap1, Keap1, is expressed in 1 baseline experiment(s);

| FBgn0038475 | ExpressionAtlas

UBR7 an E3 ligase targets Sp110 via modulating IFN beta signalling in HBV-induced hepatic carcinoma

Project description:UBR7 is an E3 ubiquitin ligase. We identified that Sp110 is a novel substrate for UBR7 which promotes HBV persistence. UBR7 ubiquitinates Sp110 which leads to downregulation of type I interferon response pathway genes. Our study reports that UBR7 ubiquitinates Sp110 thereby promoting viral persistence and HBV- induced HCC.

2023-12-31 | GSE229339 | GEO

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