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

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

PROVIDER: PRJNA842757 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19423207_1.fastq.gz	Fastqsanger.gz
	SRR19423207_2.fastq.gz	Fastqsanger.gz
	SRR19423208_1.fastq.gz	Fastqsanger.gz
	SRR19423208_2.fastq.gz	Fastqsanger.gz
	SRR19423209_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

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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.

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Regulation of metablism by mitochondrial MUL1 E3 ubiquitin ligase

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The E3 Ubiquitin Ligase AFF1 targets ARF19 to the proteasome

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EGFR is a target of the tumor suppressor E3-ligase FBXW7

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The E3 Ubiquitin Ligase AFF1 targets ARF19 to the proteasome

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