Loss of DKC1 facilitates the acquisition of metastatic traits by altering cholesterol metabolism via the mevalonate pathway
Ontology highlight
ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE207545 | GEO | 2023/01/17
REPOSITORIES: GEO
Similar Datasets
Project description:The initial dissemination of cancer cells from many primary tumors implies intravasation to lymphatic nodes or blood vessels. To investigate the mechanisms involved, we analyzed the expression of small non-coding RNAs in cutaneous squamous cell carcinoma (cSCC), a prevalent tumor that mainly spreads to lymph nodes. We report the reduced expression of small nucleolar RNAs in primary cSCCs that metastasized when compared to non-metastasizing cSCCs, and the progressive loss of DKC1 (dyskerin, which stabilizes the small nucleolar RNAs) along the metastasis. DKC1 depletion in cSCC cells triggered lipid metabolism by altering the mevalonate pathway and the acquisition of metastatic traits. Treatment of DKC1-depleted cells with simvastatin, an inhibitor of the mevalonate pathway, blocked the expression of proteins involved in the epithelial-to-mesenchymal transition. Consistently, the expression of the enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 1 was associated with pathological features of high metastatic risk in cSCC patients. Our data underpin the relevance of the mevalonate metabolism in metastatic dissemination and pave the possible incorporation of therapeutic approaches among the antineoplastic drugs used in routine patient care.
| S-EPMC9899484 | biostudies-literature
Project description:Loss of DKC1 facilitates the acquisition of metastatic traits by altering cholesterol metabolism via the mevalonate pathway
| PRJNA856131 | ENA
Project description:Metastaticsis disease remains, by far, the leading cause of all cancer-related deaths, despite being a process highly inefficient. The metastatic process is highly inefficient as the initial dissemination of cancer cells from many primary tumors involves intravasation to lymphatics nodes or blood vessels, a process poorly understood. To investigate generalthe molecular mechanisms involved in this step we analyzed the expression of the epigenetic regulators small non-coding RNAs (sncRNAs) in cutaneous squamous cell carcinoma (cSCC), a highly prevalent malignant tumor that mainly spreads to lymph nodes. Here we report the reduced expression of small nucleolar RNAs (snoRNAs) in primary cSCCs that metastasized when compared to non-metastasizing cSCCs, and the progressive loss of DKC1 (the protein that stabilizes the snoRNAs) along the metastasis of the carcinomas. DWe demonstrate that depletion of DKC1 in cSCC cells resulted in a switch totriggers lipid metabolism and the acquisition of metastatic traits. Treatment of DKC1-depleted cells with simvastatin, an inhibitor of the mevalonate pathway, blocked the expression of proteins involved in the epithelial to mesenchymal transition (EMT), suggesting that the rewiring of the lipid metabolism is required to acquire the invasion abilities. Furthermore, the expression of the enzyme HMGCS1 is associated with pathologic features of high metastatic risk in cSCC patients, underpinning the relevance of the mevalonate metabolism in the lymphatic dissemination step.
2023-01-31 | PXD034155 | Pride
Project description:Heat shock factor 1 (HSF1) is an essential transcription factor in cellular adaptation to various stresses such as heat, proteotoxic stress, metabolic stress, reactive oxygen species, and heavy metals. HSF1 promotes cancer development and progression, and increased HSF1 levels are frequently observed in multiple types of cancers. Increased activity in the mevalonate and cholesterol biosynthesis pathways, which are very important for cancer growth and progression, is observed in various cancers. However, the functional role of HSF1 in the mevalonate and cholesterol biosynthesis pathways has not yet been investigated. Here, we demonstrated that the activation of RAS-MAPK signaling through the overexpression of H-RasV12 increased HSF1 expression and the cholesterol biosynthesis pathway. In addition, the activation of HSF1 was also found to increase cholesterol biosynthesis. Inversely, the suppression of HSF1 by the pharmacological inhibitor KRIBB11 and short-hairpin RNA (shRNA) reversed H-RasV12-induced cholesterol biosynthesis. From the standpoint of therapeutic applications for hepatocellular carcinoma (HCC) treatment, HSF1 inhibition was shown to sensitize the antiproliferative effects of simvastatin in HCC cells. Overall, our findings demonstrate that HSF1 is a potential target for statin-based HCC treatment.
| S-EPMC6769575 | biostudies-literature
Project description:The mevalonate (MVA)/cholesterol pathway is crucial for central nervous system (CNS) development and function and consequently, any dysfunction of this fundamental metabolic pathway is likely to provoke pathologic changes in the brain. Mutations in genes directly involved in MVA/cholesterol metabolism cause a range of diseases, many of which present neurologic and psychiatric symptoms. This raises the question whether other diseases presenting similar symptoms are related albeit indirectly to the MVA/cholesterol pathway. Here, we summarized the current literature suggesting links between MVA/cholesterol dysregulation and specific diseases, namely autism spectrum disorder and Rett syndrome.
| S-EPMC6651320 | biostudies-literature
Project description:BackgroundDyskeratosis congenita 1 (DKC1) is dysregulated in several cancers. However, the expression and function of DKC1 in colorectal cancer (CRC) is rarely reported.MethodsTissue microarrays (TAMs) including 411 cases of CRC tissues and corresponding paracancerous tissues were used to examine the DKC1 expression. The correlations between the DKC1 expression and clinicopathological or survival characters were further analysed. The functions and molecular mechanism of DKC1 in CRC were investigated through a series of in vitro and in vivo experiments.ResultsThe result showed that DKC1 expression was increased in CRC tissues. Increased DKC1 expression was associated with high grade of TNM stage, additional lymph node metastasis, and poor prognosis of patients with CRC. Multivariate COX analysis indicated that DKC1 can act as an independent prognostic factor for patients with CRC. DKC1 also facilitated the CRC angiogenesis and metastasis by increasing HIF-1α and VEGF expression levels. Chromatin immunoprecipitation assay demonstrated that DKC1 facilitated HIF-1α expression by regulating HIF-1α promoter activity.ConclusionDKC1 appears to regulate CRC angiogenesis and metastasis through directly activating HIF-1α transcription. DKC1 can serve as an accurate indicator in predicting the prognosis of patients with CRC and act as a potential therapeutic target for CRC.
| S-EPMC7054532 | biostudies-literature
Project description:Cholesterol metabolism plays a critical role in the progression of hepatocellular carcinoma (HCC), but it is not clear how cholesterol metabolism is regulated. The tubulin beta class I genes (TUBBs) are associated with the prognosis of many different cancers. To confirm the function of TUBBs in HCC, the Kaplan-Meier method and Cox analyses were performed using TCGA and GSE14520 datasets. A higher expression of TUBB2B is an independent prognostic factor for shorter over survival in HCC patients. Deletion of TUBB2B in hepatocytes inhibits proliferation and promotes tumor cell apoptosis, while over-expression of TUBB2B has the opposite function. This result was confirmed in a mouse xenograft tumor model. Mechanistically, TUBB2B induces the expression of CYP27A1, an enzyme responsible for the conversion of cholesterol to 27-hydroxycholesterol, which leads to the up-regulation of cholesterol and the progression of HCC. In addition, TUBB2B regulates CYP27A1 via human hepatocyte nuclear factor 4alpha (HNF4A). These findings indicated that TUBB2B functions as an oncogene in HCC, and plays a role in promoting cell proliferation and anti-apoptosis through targeting HNF4A/CYP27A1/cholesterol.
| S-EPMC9986231 | biostudies-literature
Project description:Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. Both spatial retention of HMGCRs and increased mevalonate pathway flux during AGR is dependent on NVJ tether Nvj1. Furthermore, we demonstrate that HMGCRs associate into high-molecular-weight assemblies during AGR in an Nvj1-dependent manner. Loss of Nvj1-mediated HMGCR partitioning can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting the association of HMGCRs in high molecular weight assemblies. Loss of HMGCR compartmentalization perturbs yeast growth following glucose starvation, indicating it promotes adaptive metabolic remodeling. Collectively, we propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes at an inter-organelle contact site.
| S-EPMC8057812 | biostudies-literature
Project description:Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Despite the roles of G protein-coupled receptors in thymocyte emigration, the downstream signaling mechanism remains poorly defined. Here, we report the discrete roles for the two branches of mevalonate metabolism-fueled protein prenylation pathway in thymocyte egress and immune homeostasis. The protein geranylgeranyltransferase Pggt1b is up-regulated in single-positive thymocytes, and loss of Pggt1b leads to marked defects in thymocyte egress and T cell lymphopenia in peripheral lymphoid organs in vivo. Mechanistically, Pggt1b bridges sphingosine-1-phosphate and chemokine-induced migratory signals with the activation of Cdc42 and Pak signaling and mevalonate-dependent thymocyte trafficking. In contrast, the farnesyltransferase Fntb, which mediates a biochemically similar process of protein farnesylation, is dispensable for thymocyte egress but contributes to peripheral T cell homeostasis. Collectively, our studies establish context-dependent effects of protein prenylation and unique roles of geranylgeranylation in thymic egress and highlight that the interplay between cellular metabolism and posttranslational modification underlies immune homeostasis.
| S-EPMC7041713 | biostudies-literature
Project description:Malaria parasites rely on a plastid organelle for survival during the blood stages of infection. However, the entire organelle is dispensable as long as the isoprenoid precursor, isopentenyl pyrophosphate (IPP), is supplemented in the culture medium. We engineered parasites to produce isoprenoid precursors from a mevalonate-dependent pathway, creating a parasite line that replicates normally after the loss of the apicoplast organelle. We show that carbon-labeled mevalonate is specifically incorporated into isoprenoid products, opening new avenues for researching this essential class of metabolites in malaria parasites. We also show that essential apicoplast proteins, such as the enzyme target of the drug fosmidomycin, can be deleted in this mevalonate bypass parasite line, providing a new method to determine the roles of other important apicoplast-resident proteins. Several antibacterial drugs kill malaria parasites by targeting basic processes, such as transcription, in the organelle. We used metabolomic and transcriptomic methods to characterize parasite metabolism after azithromycin treatment triggered loss of the apicoplast and found that parasite metabolism and the production of apicoplast proteins is largely unaltered. These results provide insight into the effects of apicoplast-disrupting drugs, several of which have been used to treat malaria infections in humans. Overall, the mevalonate bypass system provides a way to probe essential aspects of apicoplast biology and study the effects of drugs that target apicoplast processes.
| S-EPMC7046295 | biostudies-literature