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Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the EPAC-RAP1 signaling dependency of primary melanoma

ABSTRACT: RAP guanine exchange factors EPAC1/2 (Exchange Protein Activated by cyclic AMP) are important signaling proteins. EPACs are important for the growth of cutaneous primary melanoma and loss of dependency on EPACs is associated with melanoma metastatic progression. In this study, employing transformed human melanocytes, we show that activation of EPACs is an early event in malignant transformation, and using chemical inhibition and genetic deletion of EPAC in Braf/Pten mice, we also show that EPACs promote melanoma tumor development and growth. Query of the Cancer Genome Atlas (TCGA) and immunohistochemical analysis of melanoma tumors showed that low EPAC mRNA and RAP1-GTP protein correlate with better recurrence free survival of patients with primary melanoma. RNAseq analysis of primary and metastatic melanoma cells treated with an EPAC inhibitor showed that TXNIP, an important regulator of redox homeostasis, is a downstream effector of EPAC signaling. We also show that EPACs promote melanoma growth by regulation of redox homeostasis and mitochondrial ROS through activation of mechanistic target of rapamycin complex 1 (mTORC1) that stabilizes hypoxia-inducible factor 1-alpha (HIF-1α), a transcriptional activator of TXNIP and glycolytic enzymes. Our data suggest that targeting mechanisms employed by melanoma cells to bypass EPAC dependency as a potential therapeutic approach for melanoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319527 | GEO | 2026/07/29

REPOSITORIES: GEO

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Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the EPAC-RAP1 signaling dependency of primary melanoma

Project description:Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the EPAC-RAP1 signaling dependency of primary melanoma

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Transcription profiling of human HMVEC cells treated with vascular endothelial growth factor, anthrax edema toxin, and an Epac activator

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Project description:Among vertebrate animals, mammals have retained a unique molecular change that allows an intracellular arrestin domain-containing protein to bind covalently to thioredoxin. This interaction of Thioredoxin-Interacting Protein (TXNIP) with thioredoxin can only occur when thioredoxin is in the reduced state, allowing TXNIP to "sense" the cellular oxidized environment1. Here we show that a single cysteine in TXNIP mediates the development of hepatic insulin resistance in the setting of a high fat diet (HFD). Mice with exchange of TXNIP Cysteine 247 for Serine (C247S) showed improved whole-body and hepatic insulin sensitivities compared to wildtype (WT) controls following an 8-week HFD. The inhibition of the TXNIP-thioredoxin interaction under chow and HFD also regulated plasma and liver lipids and reduced free fatty acid accumulation in the livers following HFD. These data show that mammals have a single amino acid enabling interaction of redox state with TXNIP that mediates insulin resistance in the setting of a high-fat diet. This reveals a potential evolutionarily-conserved mechanism for hepatic insulin resistance in metabolic syndromes.

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cAMP/EPAC signaling enables ETV2 to induce endothelial cells with high angiogenesis potential [RNA-seq]

Project description:Although the generation of ETV2-induced endothelial cells (iECs) from human fibroblasts serves as a novel therapeutic strategy in regenerative medicine, the process is inefficient, resulting in incomplete iEC angiogenesis. Therefore, we employed ChIP-sequencing and identified molecular mechanisms underlying ETV2-mediated endothelial transdifferentiation to efficiently produce iECs retaining appropriate functionality in long-term culture. We revealed that the majority of ETV2 targets in human fibroblasts are related to vasculature development and signaling transduction pathways including Rap1 signaling. From a screening of signaling pathway modulators, we confirmed that forskolin facilitated efficient and rapid iEC reprogramming via activation of cAMP/EPAC/RAP1 axis. The iECs obtained via cAMP signaling activation showed superior angiogenesis in vivo as well as in vitro. Moreover, these cells could form aligned endothelium along the vascular lumen ex vivo when seeded into decellularized liver scaffold. Overall, our study provided evidence that cAMP/EPAC/RAP1 axis is required for the efficient generation of iECs with angiogenesis potential.

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