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

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

PROVIDER: PRJNA474756 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7267580_1.fastq.gz	Fastqsanger.gz
	SRR7267580_2.fastq.gz	Fastqsanger.gz
	SRR7267581_1.fastq.gz	Fastqsanger.gz
	SRR7267581_2.fastq.gz	Fastqsanger.gz
	SRR7267582_1.fastq.gz	Fastqsanger.gz

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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.

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Project description:Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1alpha and HIF-2a transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1a as an inhibitor and HIF-2a 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 essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1a and HIF-2a are required for the clear cell phenotype. Transcriptomic and proteomic analyses revealed that HIF-1alpha regulates glycolysis while HIF-2a regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2a-deficient tumours were characterised by increased antigen presentation, interferon signalling and CD8+ T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlated with altered immune microenvironment in human ccRCC. These studies reveal an oncogenic role of HIF-1alpha in ccRCC initiation and suggest that alterations in the balance of HIF-1alpha and HIF-2a activities can affect different aspects of ccRCC biology and disease aggressiveness.

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Transcription profiling of human 786-O clear cell renal carcinoma cells reveals small molecule inhibitors of HIF-2a translation link its 5 UTR Iron-Responsive Element (IRE) to oxygen sensing

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