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Effects of HIF2α in renal cancer metastasis and sensitivity to repurposed drugs

ABSTRACT: Effects of HIF2α in renal cancer metastasis and sensitivity to repurposed drugs

PROVIDER: PRJNA643786 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12135913_1.fastq.gz	Fastqsanger.gz
	SRR12135913_2.fastq.gz	Fastqsanger.gz
	SRR12135914_1.fastq.gz	Fastqsanger.gz
	SRR12135914_2.fastq.gz	Fastqsanger.gz
	SRR12135915_1.fastq.gz	Fastqsanger.gz

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Effects of HIF2α in renal cancer metastasis and sensitivity to repurposed drugs

Project description:Background: in clear cell renal cell carcinoma (ccRCC), 80% of cases have biallelic inactivation of VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. Methods: we generated the 786-0 HIF2α knockout (KO) cell line and assessed the HIF2α antagonist PT2385 in several steps of tumour development. RNA sequencing was performed to identify genes differentially expressed between them and a drug screening was used to identify drugs with differential effects on HIF2α-expressing and KO cells. Results: HIF2α KO promoted cell migration, reduced proliferation and clonogenicity, as well as metastasis, whereas PT2385 treatment only inhibited tumour cell invasion. There was a large set of co-ordinately regulated genes, but HIF2α KO cells also had up-regulation of genes related to EMT and downregulation of genes involving cell migration and extracellular matrix. The HIF2α KO increased sensitivity to statins, while PT2385 had no effect. Conclusions: this study shows new pathways that could be targeted combined with PT2385 to enhance its therapeutic effects and delay resistance.

2021-08-11 | GSE153711 | GEO

Differential effects of HIF2α antagonist and HIF2α silencing in renal cancer and sensitivity to repurposed drugs.

Project description:BackgroundIn clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed.MethodsWe assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385.ResultsPT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity.Conclusionsthis study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.

| S-EPMC8344147 | biostudies-literature

BMAL1-HIF2α heterodimers contribute to ccRCC

Project description:Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by HIF2α antagonists. We show that increasing BMAL1 sensitizes ccRCC-derived A498 cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.

2025-03-17 | GSE290669 | GEO

BMAL1-HIF2α heterodimers contribute to ccRCC [ChIP-seq]

Project description:Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by HIF2α antagonists. We show that increasing BMAL1 sensitizes ccRCC-derived 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.

2025-03-17 | GSE269334 | GEO

Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs

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PRCC-TFE3 Function and the Role of HIF1α and HIF2α in TFE3-Rearranged Renal Cell Carcinoma Development

Project description:PRCC-TFE3 is an oncogenic chimeric transcription factor identified in human TFE3-rearranged renal cell carcinoma. To investigate the function of PRCC-TFE3 in vivo, we generated PRCC-TFE3 knock-in (KI) mice by inserting a loxP-STOP-loxP-PRCC-TFE3 cassette into the Rosa26 locus. When PRCC-TFE3 KI mice were crossed with Cadherin 16-Cre transgenic mice (KSP-Cre), the resulting mice developed TFE3-RCC in the kidney. Our findings revealed that hypoxia-inducible factors HIF1α and HIF2α are directly upregulated by PRCC-TFE3. To clarify the roles of HIF1α and HIF2α in TFE3-RCC development, we further crossed PRCC-TFE3 KI mice with HIF1α flox and/or HIF2α flox mice.

2025-01-07 | GSE283743 | GEO

Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling

Project description:Using a combination of single-cell RNAseq methods and murine pulmonary hypertension models, we show HIF2α overexpressing pericytes’ transformation into SMC-like cells, confirming HIF2α as a major molecular regulator in hypoxia-induced pulmonary hypertension (PH) and vascular remodeling. We demonstrate that HIF2α overexpression in pericyte-dominant transgenic mice exacerbates PH and right ventricular hypertrophy (RVH), whereas disruption of HIF2α expression attenuates the development of PH.

2024-08-25 | GSE211985 | GEO

Blood Biomarkers for Memory: Towards Early Detection of Risk for Alzheimer Disease, Pharmacogenomics, and Repurposed Drugs

Project description:Blood Biomarkers for Memory: Towards Early Detection of Risk for Alzheimer Disease, Pharmacogenomics, and Repurposed Drugs

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MYC, together with Cohesin and Mediator complexes, predetermines the sensitivity of gastrointestinal cancer to antifolate drugs

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