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ACSS2 Regulates HIF-2α Degradation through the E3-Ubiquitin Ligase MUL1 in Clear Cell Renal Cell Carcinoma

ABSTRACT: ACSS2 is a key contributor to the acetyl-CoA pool and has a role in supporting biosynthetic processes, as well as acetylation. To investigate the role of ACSS2 in regulating chromatin accessibility in ccRCC, we performed ATAC-seq on 786-O cells treated with DMSO or ACSS2i for 24 hours.

ORGANISM(S): Homo sapiens

PROVIDER: GSE204947 | GEO | 2023/05/26

REPOSITORIES: GEO

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ACSS2 Regulates HIF-2α Degradation through the E3-Ubiquitin Ligase MUL1 in Clear Cell Renal Cell Carcinoma

Project description:Clear cell renal cell carcinoma (ccRCC) is an aggressive kidney cancer driven by VHL loss and aberrant HIF-2α signaling. Acetate metabolism may contribute to this axis by ACSS2-dependent acetylation of HIF-2α and may provide opportunities to intervention. Here we tested the effects of pharmacological and genetic manipulation of ACSS2 on HIF-2α, ccRCC cells, and tumors. ACSS2 inhibition led to HIF-2α degradation and suppressed ccRCC growth in vitro, in vivo, and in primary cell cultures of ccRCC patient tumors. This treatment resulted in reduced glucose and cholesterol metabolism, mitochondrial biogenesis and altered cristae deformation, that are consistent with loss of HIF-2α. Mechanistically, HIF-2α protein levels are regulated through proteolytic degradation and we found, in parallel to VHL, HIF-2α stability was dependent on ACSS2 activity to prevent direct interaction with the E3 ligase MUL1. These findings highlight ACSS2 as a critical upstream regulator of pathogenically stabilized HIF-2α, and provides a mechanism that may be exploited to overcome resistance to HIF-2α inhibitor therapies.

2022-07-26 | ST002241 | MetabolomicsWorkbench

HIF-1α and HIF-2α differently regulate tumour development, metabolism and inflammation of clear cell renal cell carcinoma in mice

Project description:Mutational inactivation of VHL is the earliest genetic event in the majority of ccRCCs, leading to activation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCCs and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Using an autochthonous ccRCC model, we show genetically that Hif1a is necessary for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are necessary for the clear cell phenotype. Transcriptomic and proteomic analyses revealed that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. Deficiency of HIF-2α increased CD8+ T cell infiltration and activation. These studies reveal different functions of HIF-1α and HIF-2α in ccRCC. SIGNIFICANCE The roles of HIF-1α and HIF-2α in ccRCC pathogenesis remain unclear. Using a mouse genetic approach we show that HIF-1α but not HIF-2α is important for tumour formation, contrary to predictions from studies of human ccRCC. We show that HIF-1α and HIF-2α transcriptionally regulate different aspects of metabolism and identify HIF-2α as a suppressor of immune cell infiltration and activation.

2020-07-02 | PXD016630 | Pride

The OGT/HIF-2α axis promotes the progression of clear cell renal cell carcinoma and its targetable vulnerability to ferroptosis

Project description:O-GlcNAc transferase (OGT) has been reported to participate in the development of various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we found that OGT was upregulated in ccRCC compared with paired nontumor renal tissues and was associated with worse survival. Moreover, OGT promoted the proliferation, clone formation, and invasive abilities of VHL-mutated ccRCC cells. Mechanistically, OGT promoted the expression of hypoxia-inducible factor-2α (HIF-2α) (the main driver of the clear cell phenotype) by repressing ubiquitin‒proteasome system-mediated degradation. Interestingly, the OGT/HIF-2α axis confers ccRCC sensitivity to ferroptosis, rendering it vulnerable. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2α. On the other hand, the OGT/HIF-2α axis renders ccRCC vulnerable to ferroptosis, suggesting that ferroptosis inducers are a promising therapy for patients with upregulated OGT and mutated VHL ccRCC.

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Overexpression of Parkin in clear cell renal cell carcinoma decreases tumor aggressiveness by regulating CKS2 levels

Project description:Here we analyzed ccRCC 786-O cells with overexpressed Parkin in contrast to wild type and control cells. While differences between 786-O wild type and control cells were rather moderate, quite some differences were found between 786-O wild type/control cells and cells overexpressed with Parkin.

2022-02-16 | PXD029398 | Pride

Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and long-term memory [RNA-seq]

Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and direct regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Global survey of gene expression in CAD cells and differentiated CAD neurons following lentiviral knockdown of ACSS2 or ATP citrate lyase (ACL) (and control = scramble hairpin); survey of hippocampal gene expression changes associated with retrieval of fear memory, after ACSS2-AAV knockdown or in EGFP-AAV control (comparison of 0h vs. 1h post-memory retrieval).

2017-05-01 | E-GEOD-76853 | biostudies-arrayexpress

Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and long-term memory [ChIP-seq]

Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and directchum regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Genome-wide examination of histone H3 and H4 acetylation, as well as ACSS2 binding, in undifferentiated CAD cells and differentiated CAD neurons; background adjusted by H3 ChIP or Input.

2017-05-01 | E-GEOD-76850 | biostudies-arrayexpress

Structural Diversity of Ubiquitin E3 Ligase

Project description: Not available

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Ubiquitin E3 ligase FIEL1 regulates fibrotic lung injury through SUMO-E3 ligase PIAS4.

Project description: Not available

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RNA-Seq analysis of HIF-2a-responsive genes in clear-cell renal cell carcinoma

Project description:We performed RNA-Seq analysis of wildtype and three EPAS1-/- 786-O single cell clones generated by CRISPR/Cas9 to identify the HIF-2a-responsive genes in this cell line. Samples from wildtype 786-O cells treated with DMSO or HIF-2a antagonist compound C2 were also included in this analysis.

2019-03-04 | GSE115389 | GEO

NAT10 promotes the progression of clear cell renal cell carcinoma by regulating ac4C acetylation of NFE2L3 and activating AKT/GSK3β signaling pathway [RNA-seq]

Project description:In order to determine how NAT10 regulates NFE2L3 to promote the progression of ccRCC, since NFE2L3 is a transcription factor, we performed CHP-seq detection for NFE2L3, as well as RNA-seq detection for 786-O cells with stable NFE2L3 knocking and control 786-O cells. The results of RNA-seq showed that 312 transcripts in the NFE2L3 knockdown group were down-regulated, and 3 114 transcripts in the previous ccRCC tissue were up-regulated. Moreover, after comprehensive analysis of ChIP-seq, there were 12 overlapping transcripts. Analysis of the expression levels of 12 transcripts in control cells and stable NFE2L3 knockout cells showed that the expression level of LASP1 was the highest in cells, so we hypothesized that NFE2L3 promoted the progression of ccRCC by affecting LASP1.

2023-03-18 | GSE226941 | GEO

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