MITF regulates SCD and fatty acid saturation to control melanoma phenotypic state.
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PROVIDER: PRJNA565361 | ENA |
REPOSITORIES: ENA
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Project description:The ability of cancer cells to switch phenotype in response to a dynamic intra-tumor microenvironment is a major barrier to effective therapy. In melanoma, down-regulation of the lineage addiction oncogene MITF (Microphthalmia-associated transcription factor) is a hallmark of the proliferative-to-invasive phenotype switch. Yet how MITF promotes proliferation and suppresses invasion is poorly understood. Here we show that expression of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) is activated by MITF, but suppressed by the stress-responsive transcription factor ATF4. SCD expression is required for MITF-positive melanoma cell proliferation,. By contrast, MITF-low cells express reduced levels of SCD and are insensitive to its inhibition, indicating that cell phenotype dictates response to drugs targeting lipid metabolism. Since SCD suppresses inflammatory signalling and ATF4 expression, the results identify a positive feedback-loop that can maintain an invasive phenotype, uncover a key role for MITF and ATF4 in metabolic reprograming, and reveal fatty acid composition as a driver of melanoma phenotype-switching.
2019-11-19 | PXD010254 | Pride
Project description:Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. Yet how metabolism is implicated in specific phenotypes, and whether lineage-restricted mechanisms control key metabolic vulnerabilities remains poorly understood. In melanoma, down-regulation of the lineage addiction oncogene Microphthalmia-associated Transcription Factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, though how MITF promotes proliferation and suppresses invasion is poorly defined. Here we show that MITF is a lineage restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD), and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signalling, and an ATF4-mediated feedback-loop that maintains dedifferentiation. Our results reveal that MITF is a lineagespecific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype-switching, and highlight that cell phenotype dictates response to drugs targeting lipid metabolism.
2019-10-16 | GSE137390 | GEO
Project description:Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity
| PRJNA565365 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-10-16 | GSE137392 | GEO
Project description: Not available
| S-EPMC7137507 | biostudies-literature
Project description:Background The composition of intramuscular fat depends on genetic and environmental factors, including the diet. In pigs, we identified a haplotype of three SNP mutations in the steaoryl-coA desaturase (SCD) gene promoter associated with higher content of monounsaturated fatty acids in intramuscular fat. The second of these three SNPs (rs80912566, C>T) affected a putative retinol response element in the SCD promoter. The effect of dietary vitamin A restriction over intramuscular fat content is controversial in pigs as it seems to depend on the genetic line and the duration of the restriction. This study aims to investigate changes in the muscle transcriptome in SCD rs80912566_TT and CC pigs fed with and without vitamin A supplement during the fattening period. Results Vitamin A did not affect carcass fattening traits and fatty acid composition in muscle, but we observed an interaction between vitamin A and SCD genotype on the desaturation of muscle fatty acids. The diet without vitamin A supplement tended to enlarge the compositional differences between genotypes. The interaction between diet and genotype was also evident at the transcriptome level, the highest number of differentially expressed genes were detected between SCD rs80912566_TT pigs fed with the two diets. Conclusions Restricting dietary vitamin A during the fattening period did not improve intramuscular fat content despite relevant changes in muscle gene expression, both in coding and non-coding genes. Despite this, there was a significant interaction between the SCD genotype and the dietary vitamin A, which affected the quality of the meat through a change in the saturation index of intramuscular fat and activated general pathways of retinol response in a SCD genotype-dependant manner.
2021-09-12 | GSE183909 | GEO
Project description:The impact of various fatty acid types on adaptive immunity remains uncertain, and their roles remain unelucidated. In this study, we showed that the enzyme stearoyl-CoA desaturase-1 (Scd-1) and its resulting compound, oleic acid (OA), have a substantial impact on the transformation of CD8+ naïve T cells into effector T cells. Inactivation of Scd-1 triggers the specialization of CD8+ T cells into the Teff subset, enhancing the effector function and mitochondrial metabolism of Teff cells, and OA can partially counteract this.
2024-01-25 | GSE253770 | GEO
Project description:In response to the dynamic intra-tumor microenvironment, melanoma cells adopt different phenotypic states possessing distinct biological properties associated with differential expression of the microphthalmia-associated transcription factor (MITF). The response to hypoxia, a major microenvironmental cue, is underpinned by expression of hypoxia-inducible transcription factors (HIFs) that reprogram metabolism and promote pro-angiogenic VEGF expression. HIF1 indirectly represses MITF via the transcription factor bHLHE40/DEC1, and MITF can activate HIF1 expression. Although HIF and MITF share a highly related DNA-binding specificity, it is unclear whether they share a subset of target genes. Moreover, the genome-wide impact of hypoxia on melanoma, which genes are direct HIF targets, and whether melanoma cell lines representing different phenotypic states exhibit distinct hypoxic responses is unknown. Here we show, that three different melanoma cell lines exhibit widely different hypoxia responses with only a core 23 genes regulated in common after 12 h in hypoxia. Surprisingly, under hypoxia MITF is transiently up-regulated by HIF1 and co-regulates a subset of HIF targets including VEGFA. Significantly, we also show that MITF represses itself and also regulates SDHB to control the TCA cycle and suppress pseudo-hypoxia. Our results reveal a previously unsuspected role for MITF in metabolism and the network of factors underpinning the hypoxic response in melanoma.
2019-06-13 | GSE132624 | GEO
Project description:NHLBI TOPMed: Outcome Modifying Gene in SCD (OMG-SCD)
| PRJNA472123 | ENA
Project description:NHLBI TOPMed: Outcome Modifying Gene in SCD (OMG-SCD)
| PRJNA472122 | ENA