HIF-1α binding in suspended MDA-MB-231 breast cancer cells
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ABSTRACT:
PROVIDER: PRJNA1119025 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29254589_1.fastq.gz | Fastqsanger.gz | |||
| SRR29254589_2.fastq.gz | Fastqsanger.gz |
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Project description:We report the transcriptional differences of suspended MCF-7 and MDA-MB-231 breast cancer cells after treated with CoCl2 100uM for 24 hours.
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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-1α in colon, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-1α+/+, Hif-1αLSL/LSL mice. Background & Aims: The progression and growth of solid tumors leads to a state where tumors outgrow their capacity for efficient oxygenation and nutrient uptake and an increase in tumor hypoxia. Tumor hypoxic response is mediated by hypoxia-inducible factor (HIF)-1a and HIF-2a. These transcription factors regulate a battery of genes that are critical for tumor oxygenation, tumor metabolism, and cell proliferation and survival. Therefore, inhibitors of HIF have been sought for as anti-neoplastic agents in several different kinds of cancers. Interestingly, in ischemic and inflammatory diseases of the intestine, activation of HIF-1a is beneficial, and can reduce intestinal inflammation. The efficacy of pharmacological agents that chronically activate HIF-1a are decreased due to the tumorigenic potential of HIF. However, recent advance in understanding HIF signaling have identified mechanisms, which could allow for isoform specific activators. Activation of HIF-2a increases colon carcinogenesis and progression in mouse models. However, the role of chronic HIF-1a activation is unclear in the progression in colon cancer. The present data demonstrates that activation of HIF-1a in epithelial cells does not increase colon carcinogens or progression in two mouse models of colon cancer, and provides the proof of principle that HIF-1a activation maybe safe as therapies for inflammatory bowel disease. Global gene expression profiling in colon RNAs isolated from 6- to 8-week-old Hif-1α+/+ (n=5, Shah 019) and Hif-1αLSL/LSL (n=5, Shah 020).
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Project description:Analysis of Huh-7 hepatocarcinoma cell line depleted of NDRG3 or HIF-1α under hypoxic condition. HIF-1α and NDRG3 have distinct functions in hypoxia responses. Results provide insight into molecular basis of HIF-independent signaling in the development and progression of hypoxic tumors Gene expression profiles of Huh-7 cells stably expressing NDRG3-shRNA or HIF-1α-shRNA under normoxia were compared to gene expression profiles of Huh-7 stable cells under hypoxia for 6, 12 and 24 hours.
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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.
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Project description:Hypoxia-inducible factor-1 (HIF-1) is a master regulator of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1α-mediated transactivation and glycolysis. Mechanistically, HIFAL recruits PHD3 to PKM2 to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with hnRNPF to enhance HIF-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1α significantly rescues their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment.
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Project description:The adaptive responses to oxygen depletion orchestrated by hypoxia-inducible factors (HIFs) produce profound effects on multiple pathways. A canonical metabolic response is enhanced fermentation, but this can generate an unfavorably acidic environment under poor capillary perfusion. It is unclear how cells balance the metabolic benefits of hypoxic responses against knock-on consequences on acid-base homeostasis. We studied the interplay between hypoxia and acidosis on HIF signaling in colorectal cancer cell lines that can survive acidic conditions. Hypoxia stabilized HIF-1α, but this effect was transient in combination with acidosis. By 48 h, HIF-1α induction decreased in proportion to acidification. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (CA9, PDK1), but these did not reflect a proteome-wide downregulation. Responses to acidosis and hypoxia were enriched in lysosomal proteins, but not proteasomal components, implicating the former degradation pathway in transient HIF-1α activation under acidosis. Moreover, HIF-1α decay was not due to decreased HIF1A transcription but was blocked by lysosomal inactivation (bafilomycin-A1). Acidotic hypoxia increased the abundance of lysosomes and activated autophagy by disabling the inhibitory influence of mammalian target of rapamycin complex 1, resulting in HIF-1α degradation. By blocking HIF-driven fermentative upregulation, this mechanism protects the cellular environment from deleterious acid-overloading, an outcome that outweighs the biosynthetic benefits of raised glycolytic flux under suppressed respiration. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling, but may not reflect tumor microenvironment chemistry. Consequently, acidic hypoxic tumor regions may not necessarily overlay with sites of HIF induction
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