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

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.