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HDAC7 promotes renal cancer metastasis by reprogramming branched-chain amino acid metabolism

ABSTRACT: HDAC7 promotes renal cancer metastasis by reprogramming branched-chain amino acid metabolism

PROVIDER: PRJNA1235210 | ENA |

REPOSITORIES: ENA

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HDAC7 promotes renal cancer metastasis by reprogramming branched-chain amino acid metabolism

Project description:Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, exhibits significant metabolic reprogramming. We previously reported elevated HDAC7, a class II histone deacetylase, in ccRCC. Here, we demonstrate that HDAC7 promotes aggressive phenotypes and in vivo tumor progression in RCC. HDAC7 suppresses the expression of genes mediating branched-chain amino acid (BCAA) catabolism. Notably, lower expression of BCAA catabolism genes is strongly associated with worsened survival in ccRCC. Suppression of BCAA catabolism promotes expression of SNAIL1, a central mediator of aggressive phenotypes including migration and invasion. HDAC7-mediated suppression of the BCAA catabolic program promotes SNAI1 mRNA transcription via NOTCH signaling activation. Collectively, our findings provide new insights into the role of metabolic remodeling in ccRCC tumor progression.

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Impact of Preoperative Oral Branched-chain Amino Acids on Reducing Postoperative Insulin Resistance.

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Reprograming of Proteasomal Degradation by Branched Chain Amino Acid Metabolism

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Dynamic partitioning of branched-chain amino acids- derived nitrogen supports renal cancer progression

Project description:Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies.

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Reprograming of Proteasomal Degradation by Branched Chain Amino Acid Metabolism

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Dynamic partitioning of branched-chain amino acids- derived nitrogen supports renal cancer progression

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The Effect of Branched Chain Amino Acid to the Perioperative Nutritional Status: In Patients with Cirrhosis Undergoing Liver Resection and Patients Awaiting Liver Transplantation.

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Branched chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control

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