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Dysregulated 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) protect head and neck cancer from Endoplasmic Reticulum stress and apoptotic cell death

ABSTRACT: Dysregulated 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) protect head and neck cancer from Endoplasmic Reticulum stress and apoptotic cell death

PROVIDER: PRJNA1204948 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31862164_1.fastq.gz	Fastqsanger.gz
	SRR31862164_2.fastq.gz	Fastqsanger.gz
	SRR31862165_1.fastq.gz	Fastqsanger.gz
	SRR31862165_2.fastq.gz	Fastqsanger.gz
	SRR31862166_1.fastq.gz	Fastqsanger.gz

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Dysregulated 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) protect head and neck cancer from Endoplasmic Reticulum stress and apoptotic cell death

Project description:Altered metabolic pathways that cancer cells reply on for survival and growth are useful targets for therapeutic intervention. Here we show that de novo cholesterol biosynthesis pathways in head and neck squamous cell carcinoma (HNSCC) are highly increased to support tumor survival. Transcriptomics profiling of tumor tissues isolated from patients with HNSCC identified steroid/cholesterol metabolism as the most significantly altered metabolic pathways when compared with paired normal tissues. Disruption of two key enzymes 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) that are elevated and involved in de novo cholesterol biosynthesis using genetic approach or small inhibitory molecules (AY9944 or triparanol) results in increased apoptosis of HNSCC cells despite of replenished cholesterol. Metabolic signatures of cholesterol identified accumulated intracellular 7-dehydrocholesterol (7-DHC), a substrate of DHCR7, when either DHCR7 or DHCR24 is inhibited. Further exogenous 7-DHC supplementation decreased cancer cell viability causing cell death by inducing ER stress through eIF2alpha and IRE1 phosphorylation in HNSCC cells. This study revealed that HNSCC manages ER stresses via elevated cholesterol biosynthesis in order to remove 7-DHC for cancer viability. Our finding suggests that the metabolic intermediates in de novo cholesterol synthesis are metabolic vulnerability of HNSCC to induce ER stress and apoptosis as a potential therapeutic strategy. This study provides the evidence of direct link between the cholesterol metabolism and ER stress for cancer cell viability, suggesting metabolic vulnerability of HNSCC.

2025-04-01 | GSE285603 | GEO

3 β-hydroxysteroid-Δ 24 reductase (DHCR24) protects neuronal cells from apoptotic cell death induced by endoplasmic reticulum (ER) stress.

Project description:3β-Hydroxysteroid-Δ24 reductase (DHCR24) is an endoplasmic reticulum (ER)-localized multifunctional enzyme that possesses anti-apoptotic and cholesterol-synthesizing activities. Accumulating evidence suggests that ER stress is involved in the pathogenesis of neurodegenerative disease. In this study, we investigated whether DHCR24 may function as a neuroprotective protein under ER stress. Neuroblastoma N2A cells were infected with adenovirus expressing myc-tagged DHCR24 (Ad-DHCR24) or lacZ (Ad-lacZ, serving as a control) and subjected to ER-stress, induced with Tunicamycin (TM). Cells infected with Ad-DHCR24-myc were resistant to TM-induced apoptosis, and showed weaker level of caspase-12 activity. These cells also exhibited lower levels of Bip and CHOP proteins than Ad-LacZ-infected cells. Moreover, a stronger and rapid activation of PERK, and a prolonged activation of JNK and p38 were observed in Ad-LacZ-infected cells. The generation of intracellular reactive oxygen species from ER stress was also diminished by the overexpression of DHCR24. Additionally, intracellular cholesterol level was also elevated in the Ad-DHCR24-infected cells, accompanied by a well-organized formation of caveolae (cholesterol-rich microdomain) on the plasma membrane, and improved colocalization of caveolin-1 and insulin-like growth factor 1 receptor. These results demonstrated for the first time that DHCR24 could protect neuronal cells from apoptosis induced by ER stress.

| S-EPMC3906068 | biostudies-literature

Impact of liver-specific deletion of Dhcr24 gene on tissue gene expression

Project description:Genetic loss of the enzyme 3ß-hydroxysterol-∆24 reductase (DHCR24) results in Desmosterolosis (MIM #602398), a rare disease that presents with multiple congenital anomalies. Earlier studies to create a Dhcr24 global knockout mouse have failed as the pups died within 24 h of birth from lethal dermopathy. We generated a conditional knockout mouse model (Dhcr24flx/flx) and validated it by creating a liver-specific knockout Dhcr24flx/flx, Alb-Cre mouse using a mouse expressing cre recombinase driven by the albumin promoter. Despite increased circulatory and liver desmosterol due to loss of cholesterol synthesis in the liver, these mice demonstrated no marked changes in growth, fertility, hepatic architecture, lipoprotein secretion, etc. RNA-Seq analysis of the female mouse liver revealed no notable perturbations in pathways participating in cholesterol biosynthesis.

2020-09-04 | GSE146524 | GEO

Trans-2-enoyl-CoA reductase limits Ca2+ accumulation in the endoplasmic reticulum by inhibiting SERCA2b Ca2+ pump

Project description:The endoplasmic reticulum (ER) contains various enzymes that metabolize fatty acids (FAs). How FA metabolic enzymes cooperate with other ER functions, such as calcium (Ca2+) accumulation and its regulated release to the cytosol, is elusive. Trans-2-enoyl-CoA reductase (TER) is a FA reductase present in the ER membrane, and catalyzes the last step of FA elongation cycle and sphingosine degradation pathway. Here we show that TER directly binds to an ER Ca2+ pump, sarco(endo)plasmic reticulum Ca2+-ATPase 2b (SERCA2b), and regulates its activity. Thapsigargin, a specific SERCA inhibitor, inhibits this binding. TER binds to SERCA2b through its conserved C-terminal region. TER overexpression suppresses SERCA2b ATPase activity in microsomal membranes. Depletion of TER increases the ER Ca2+ storage and accelerates SERCA2b-dependent Ca2+ uptake to the ER after ligand-induced Ca2+ release. These results demonstrate that TER is a negative regulator of SERCA2b, implying the direct linkage of FA metabolism and Ca2+ accumulation in the ER.

2021-01-13 | PXD020792 | Pride

Hepatitis C virus NS3-4A protease regulates the lipid environment for RNA replication by cleaving host enzyme 24-dehydrocholesterol reductase

Project description:Analysis of excised gel of overexpressed and immunoprecipated 24-dehydrocholesterol reductase (DHCR24).

2020-05-28 | MSV000085492 | MassIVE

ERdj5 protects goblet cells from endoplasmic reticulum stress-mediated apoptosis under inflammatory conditions

Project description:Endoplasmic reticulum stress is closely associated with the onset and progression of inflammatory bowel disease. ERdj5 is an endoplasmic reticulum-resident protein disulfide reductase that mediates the cleavage and degradation of misfolded proteins. Although ERdj5 expression is significantly higher in the colonic tissues of patients with inflammatory bowel disease than in healthy controls, its role in inflammatory bowel disease has not yet been reported. Hence, in the current study, we utilized ERdj5-knockout mice to investigate the potential roles of ERdj5 in inflammatory bowel disease. ERdj5 deficiency causes severe inflammation in mouse colitis models and weakens gut barrier function by increasing NF-κB-mediated inflammation. ERdj5 may not be indispensable for goblet cell function under steady-state conditions, while its deficiency induces goblet cell apoptosis under inflammatory stimuli.

2023-06-14 | GSE224087 | GEO

Ribosome footprinting in the cytosol and endoplasmic reticulum

Project description:In eukaryotic cells, the spatial regulation of protein expression is frequently conferred through the coupling of mRNA localization and the local control of translation. mRNA localization to the endoplasmic reticulum (ER) is a prominent example of such regulation and serves a ubiquitous role in segregating the synthesis of secretory and integral membrane proteins to the ER. Recent genomic and biochemical studies have now expanded this view to suggest a role for the ER in global protein synthesis. We have utilized cell fractionation and ribosome profiling to obtain a genomic survey of the subcellular organization of mRNA translation and report that ribosomal loading of mRNAs, a proxy for mRNA translation, is biased to the ER. Notably, ER-associated mRNAs encoding both cytosolic and topogenic signal-encoding proteins display similar ribosome loading densities, suggesting that ER-associated ribosomes serve a global role in mRNA translation. We propose that the partitioning of mRNAs and their translation between the cytosol and ER compartments may represent a novel mechanism for the post-transcriptional regulation of gene expression. HEK293 cells were fractionated between the cytosol and endoplasmic reticulum. Within each fraction, ribosome footprints were generated and sequenced. In parallel, total mRNA was sequenced.

2011-12-20 | E-GEOD-31539 | biostudies-arrayexpress

New compounds triggering endoplasmic reticulum stress exert anti-melanoma effects and overcome BRAF inhibitor resistance

Project description:We discovered and developed a new series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all tested melanoma cells including those isolated from patients and those that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases endoplasmic reticulum (ER) stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms. Profiling of 3 human melanoma cell lines (SKMel28, Mel501, A375) treated with HA15 at 10 uM or with DMSO was performed using whole genome human microarrays. Cells were incubated with DMSO or HA15 for 6h and then lysed prior to RNA isolation, labelling and hybridization on microarrays. One color experiment, total of 6 samples.

2016-06-01 | E-GEOD-79071 | biostudies-arrayexpress

CDIP1-BAP31 complex transduces apoptotic signals from endoplasmic reticulum to mitochondria under endoplasmic reticulum stress.

Project description:Resolved endoplasmic reticulum (ER) stress response is essential for intracellular homeostatic balance, but unsettled ER stress can lead to apoptosis. Here, we show that a proapoptotic p53 target, CDIP1, acts as a key signal transducer of ER-stress-mediated apoptosis. We identify B-cell-receptor-associated protein 31 (BAP31) as an interacting partner of CDIP1. Upon ER stress, CDIP1 is induced and enhances an association with BAP31 at the ER membrane. We also show that CDIP1 binding to BAP31 is required for BAP31 cleavage upon ER stress and for BAP31-Bcl-2 association. The recruitment of Bcl-2 to the BAP31-CDIP1 complex, as well as CDIP1-dependent truncated Bid (tBid) and caspase-8 activation, contributes to BAX oligomerization. Genetic knockout of CDIP1 in mice leads to impaired response to ER-stress-mediated apoptosis. Altogether, our data demonstrate that the CDIP1/BAP31-mediated regulation of mitochondrial apoptosis pathway represents a mechanism for establishing an ER-mitochondrial crosstalk for ER-stress-mediated apoptosis signaling.

| S-EPMC3833439 | biostudies-literature

Next Generation Sequencing Quantitative Analysis of altered expression of genes in DHCR24 overexpressing bladder cancer cells

Project description:Bladder cancer (BCa) is one of the most commonly diagnosed urinary malignancies with an estimated yearly 550,000 new cases worldwide. Previous study revealed that DHCR24 was a crucial oncogene that widely involved in tumor initiation and progression. Yet the biological role and underlying regulatory mechanism of DHCR24 in lymph node (LN) metastasis of bladder cancer (BCa) remain unclear. Our study aims to explore the target genes of DHCR24 and the underlying mechanism in the LN metastasis of BCa.

2023-11-10 | GSE219211 | GEO

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