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WDR5 facilitates cholangiocarcinoma metastasis and EMT by promoting HIF-1α accumulation via directly interaction with c-Myc and HDAC2-PHD2 axis

ABSTRACT: WDR5 facilitates cholangiocarcinoma metastasis and EMT by promoting HIF-1α accumulation via directly interaction with c-Myc and HDAC2-PHD2 axis

PROVIDER: PRJNA628996 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11635826_1.fastq.gz	Fastqsanger.gz
	SRR11635826_2.fastq.gz	Fastqsanger.gz
	SRR11635827_1.fastq.gz	Fastqsanger.gz
	SRR11635827_2.fastq.gz	Fastqsanger.gz
	SRR11635828_1.fastq.gz	Fastqsanger.gz

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WDR5 facilitates cholangiocarcinoma metastasis and EMT by promoting HIF-1α accumulation via directly interaction with c-Myc and HDAC2-PHD2 axis

Project description:WDR5 was an important co-factor for c-Myc-induced transcriptional activation and malignant progression. We analyzed the differentially expressed genes in scramble and shWDR5 QBC-939 cells.

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Oncometabolite succinylacetone activates HIF-1α signaling and promotes angiogenesis in GSTZ1-deficient HCC

Project description:We describe a unique regulation of the succinylacetone/PHD2/HIF-1α axis by a metabolic enzyme GSTZ1. The total RNA was isolated from HepG2 cells stably transfected with or without GSTZ1-KO and analyzed using RNA-seq. Our work demonstrates that GSTZ1-deficient promotes HCC angiogenesis through stabilizing HIF-1α due to succinylacetone accumulation. In addition, the combination of targeting HIF-1α and PD-L1 could limit tumorigenesis and progression for Gstz1-/-mice, thus providing a potential target for HCC therapy.

2023-11-06 | GSE192760 | GEO

Prolyl hydroxylase domain enzyme PHD2 inhibits proliferation and metabolism in non–small cell lung cancer cells in HIF-dependent and HIF-independent manner

Project description:Prolyl hydroxylase domain protein 2 (PHD2) is one of the intracellular oxygen sensors that mediates proteasomal degradation of hypoxia-inducible factor (HIF)-α via hydroxylation under normoxia. Because of its canonical function in the hypoxia signaling pathway, PHD2 is generally regarded as a tumor suppressor. However, the effects of PHD2 in tumorigenesis are not entirely dependent on HIF-α. Based on the data obtained from The Cancer Genome Atlas (TCGA) database, we found that the expression of PHD2 is upregulated in non-small cell lung cancer (NSCLC), which accounts for approximately 80-85% of lung cancers, suggesting that PHD2 may play an important role in NSCLC. However, the function of PHD2 in NSCLC remains largely unknown. In this study, we established PHD2-deficient H1299 cells to investigate the function of PHD2 in NSCLC, and found that PHD2 suppressed cell proliferation and metabolism, but induced ROS levels in human NSCLC cells. Further results indicated that the function of PHD2 in NSCLC is dependent on its enzymatic activity and partially independent of HIF. Moreover, we performed RNA-seq and transcriptomics analysis to explore the underlying mechanisms, and identified some potential targets and pathways regulated by PHD2, apart from the canonical HIF-mediated hypoxia signaling pathway. These results provide some clues to uncover novel roles of PHD2 in lung cancer progression.

2024-07-17 | GSE239389 | GEO

Gene Expression profiles of colon from Hif-1α+/+, Hif-1αLSL/LSL

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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Effect of NDRG3 or HIF-1α knockdown on cell response to hypoxia

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WDR5 promotes histone deacetylation via direct interaction with HDAC2 in human CCA cells.

Project description:As an essential component of histone methyltransferase complex SET1/MLL, WDR5 participates in histone 3 lysine 4 methylation (H3K4me) and promotes transcription by generating an open chromatin structure and enabling better access to the transcriptional machinery. Moreover, WDR5 interacts with histone deacetylases (HDACs) to promotes histone deacetylation, which induces the compact state of nucleosome, thus represses DNA transcription. However, the modulation of WDR5 on histone methylation and acetylation is tissue- and context-specific, and this function has not been elucidated in cholangiocarcinoma yet.

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Cystathione β-synthase regulates HIF-1α stability through persulfidation of PHD2.

Project description:The stringent expression of the hypoxia inducible factor-1α (HIF-1α) is critical to a variety of pathophysiological conditions. We reveal that, in normoxia, enzymatic action of cystathionine β-synthase (CBS) produces H2S, which persulfidates prolyl hydroxylase 2 (PHD2) at residues Cys21 and Cys33 (zinc finger motif), augmenting prolyl hydroxylase activity. Depleting endogenous H2S either by hypoxia or by inhibiting CBS via chemical or genetic means reduces persulfidation of PHD2 and inhibits activity, preventing hydroxylation of HIF-1α, resulting in stabilization. Our in vitro findings are further supported by the depletion of CBS in the zebrafish model that exhibits axis defects and abnormal intersegmental vessels. Exogenous H2S supplementation rescues both in vitro and in vivo phenotypes. We have identified the persulfidated residues and defined their functional significance in regulating the activity of PHD2 via point mutations. Thus, the CBS/H2S/PHD2 axis may provide therapeutic opportunities for pathologies associated with HIF-1α dysregulation in chronic diseases.

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Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α.

Project description:Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome's interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors-vadadustat and roxadustat-to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.

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The HIF-1α antisense long non-coding RNA drives a positive feedback loop of HIF-1α mediated transactivation and glycolysis

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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WDR5 promotes histone deacetylation via direct interaction with HDAC2 in human CCA cells.

Project description:WDR5 promotes histone deacetylation via direct interaction with HDAC2 in human CCA cells.

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