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Lineage factor functions in renal carcinoma - ChIP-seq

ABSTRACT: The oncogenic potential of cancer-associated genetic alterations displays strong tissue-selectivity, the origins of which remain poorly understood. Here, we demonstrate that the lineage transcription factor PAX8 is essential for oncogenic signaling downstream of the most common genetic alterations causing clear cell renal cell carcinoma (ccRCC). Through interaction at a distal enhancer element PAX8 facilitates CCND1 expression by HIF2A, an oncogenic driver that is genetically activated due to VHL loss in ~90% of ccRCCs. PAX8 binding at this enhancer which mediates HIF2A-dependent ccRCC formation is inhibited by the common ccRCC protective allele C at rs7948643. In addition, PAX8 supports MYC expression in ccRCC through HNF1B, another renal lineage factor. Transcriptional lineage factors are thus critical determinants of the tissue-specific cancer risk associated with somatic and inherited genetic variants. Our data also suggest that lineage factors could be targeted for therapeutic inhibition of canonical oncogenic drivers such as MYC and CCND1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163487 | GEO | 2022/03/11

REPOSITORIES: GEO

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Lineage factor-dependent signalling by kidney cancer-associated genetic alteration

Project description:As shown by large-scale human genetic data, cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analysis of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common clear cell renal cell carcinoma (ccRCC)-causing genetic alterations in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL). VHL loss, observed in ~90% of ccRCCs, can lead to hypoxia-inducible factor 2 alpha (HIF2A) stabilization. We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3. These results demonstrate that transcriptional lineage factors are essential for the expression of canonical oncogenes and they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants

2022-03-14 | PXD029522 | Pride

Lineage factor functions in renal carcinoma - ATAC-seq

Project description:The oncogenic potential of cancer-associated genetic alterations displays strong tissue-selectivity, the origins of which remain poorly understood. Here, we demonstrate that the lineage transcription factor PAX8 is essential for oncogenic signaling downstream of the most common genetic alterations causing clear cell renal cell carcinoma (ccRCC). Through interaction at a distal enhancer element PAX8 facilitates CCND1 expression by HIF2A, an oncogenic driver that is genetically activated due to VHL loss in ~90% of ccRCCs. PAX8 binding at this enhancer which mediates HIF2A-dependent ccRCC formation is inhibited by the common ccRCC protective allele C at rs7948643. In addition, PAX8 supports MYC expression in ccRCC through HNF1B, another renal lineage factor. Transcriptional lineage factors are thus critical determinants of the tissue-specific cancer risk associated with somatic and inherited genetic variants. Our data also suggest that lineage factors could be targeted for therapeutic inhibition of canonical oncogenic drivers such as MYC and CCND1.

2022-03-11 | GSE163485 | GEO

Lineage factor functions in renal carcinoma [II]

2022-03-11 | GSE163000 | GEO

Lineage factor functions in renal carcinoma [I]

2022-03-11 | GSE162948 | GEO

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

HIF-1a and HIF-2a 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 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.

2020-05-22 | GSE150983 | GEO

To identify genes responsive to treatment with the HIF2a inhibitor PT2399

Project description:HIF2a function is both necessary and sufficient for the growth of VHL-null clear cell Renal Cell Carcinoma (ccRCC). Targeting HIF2a function can therefore be a promising therapeutic strategy. We used microarray analysis to characterize a novel pharmacological inhibitor of HIF2a named PT2399. By comparing genes that are responsive to PT2399 in parental cells vs cells lacking HIF2a, by virtue of CRISPR-mediated genetic editing, we characterized gene signatures that are regulated by PT2399 in a HIF2a dependent manner. Cells were treated with either DMSO (control) or 2uM PT2399 for indicated time periods, total RNA was extracted and analyzed. Please note that the experiments with 786O Parental and HIF2a null cells were conducted independently.

2016-07-03 | E-GEOD-72959 | biostudies-arrayexpress

To identify genes responsive to treatment with the HIF2a inhibitor PT2399

2016-01-01 | GSE72959 | GEO

Genome-wide microRNA expression analysis of clear cell Renal Cell Carcinoma by next generation deep sequencing

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2012-06-21 | E-GEOD-37616 | biostudies-arrayexpress

miRNA expression in primary renal carcinomas, subgrouped based on HIF1α expression

Project description:Clear cell renal cell carcinoma (ccRCC), the most common type of renal cancer is often associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), leading to stable expression of hypoxia inducible factors, HIF1α and HIF2α. Although HIF1α functions as a tumor suppressor gene, majority of ccRCCs constitutively express HIF1α, stratifying VHL-deficient ccRCCs into groups which express either both HIF1α and HIF2α (H1H2) or HIF2α exclusively (H2). MicroRNA (miRNA) profiling performed in these two ccRCC subtypes to identify novel molecular mechanisms. ccRCCs were classified into H1H2 and H2 subtypes by immunohostochemical staining of H1F1α and H1F2α expression. Five H1H2 tumor samples and eight H2 tumor samples were used for the study. Matched adjacent normal renal tissues were used as respective controls.

2013-09-30 | E-GEOD-47582 | biostudies-arrayexpress

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