Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature. 2015;527:186–91.
Google ScholarÂ
Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C, et al. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med. 2015;7:308re308.
Robichaux WG 3rd, Cheng X. Intracellular cAMP sensor EPAC: physiology, pathophysiology, and therapeutics development. Physiol Rev. 2018;98:919–1053.
Google ScholarÂ
Almahariq M, Mei FC, Wang H, Cao AT, Yao S, Soong L, et al. Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression. Biochem J. 2015;465:295–303.
Google ScholarÂ
Yang Z, Kirton HM, Al-Owais M, Thireau J, Richard S, Peers C, et al. Epac2-Rap1 signaling regulates reactive oxygen species production and susceptibility to cardiac arrhythmias. Antioxid Redox Signal. 2017;27:117–32.
Google ScholarÂ
Almahariq M, Chao C, Mei FC, Hellmich MR, Patrikeev I, Motamedi M, et al. Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo. Mol Pharmacol. 2015;87:142–9.
Google ScholarÂ
Krishnan A, Bhasker AI, Singh MK, Rodriguez CI, Perez EC, Altameemi S, et al. EPAC regulates melanoma growth by stimulating mTORC1 signaling and loss of EPAC signaling dependence correlates with melanoma progression. Mol Cancer Res. 2022;20:1548–60.
Google ScholarÂ
Rodriguez CI, Castro-Perez E, Prabhakar K, Block L, Longley BJ, Wisinski JA, et al. EPAC-RAP1 axis-mediated switch in the response of primary and metastatic melanoma to cyclic AMP. Mol Cancer Res. 2017;15:1792–802.
Google ScholarÂ
Stokman G, Qin Y, Booij TH, Ramaiahgari S, Lacombe M, Dolman ME, et al. Epac-Rap signaling reduces oxidative stress in the tubular epithelium. J Am Soc Nephrol. 2014;25:1474–85.
Google ScholarÂ
Herlyn M, Balaban G, Bennicelli J, Dt Guerry, Halaban R, Herlyn D, et al. Primary melanoma cells of the vertical growth phase: similarities to metastatic cells. J Natl Cancer Inst. 1985;74:283–9.
Google ScholarÂ
Devi S, Markandeya Y, Maddodi N, Dhingra A, Vardi N, Balijepalli RC, et al. Metabotropic glutamate receptor 6 signaling enhances TRPM1 calcium channel function and increases melanin content in human melanocytes. Pigment Cell Melanoma Res. 2013;26:348–56.
Google ScholarÂ
Yan J, Mei FC, Cheng H, Lao DH, Hu Y, Wei J, et al. Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1. Mol Cell Biol. 2013;33:918–26.
Google ScholarÂ
Dankort, Curley D, Cartlidge DP, Nelson RA, Karnezis B, Damsky AN, et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41:544–52.
Google ScholarÂ
Rodriguez CI, Castro-Perez E, Longley BJ, Setaluri V. Elevated cyclic AMP levels promote BRAF(CA)/Pten(-/-) mouse melanoma growth but pCREB is negatively correlated with human melanoma progression. Cancer Lett. 2018;414:268–77.
Google ScholarÂ
Martin M. CUTADAPT removes adapter sequences from high-throughput sequencing reads. EMBnetjournal. 2011;17:10–12.
Andrews S.Babraham Bioinformatics. https://www.bioinformatics.babraham.ac.uk/index.html
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.
Google ScholarÂ
Anders S, Pyl PT, Huber W. HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.
Google ScholarÂ
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
Google ScholarÂ
Wang L, Wang S, Li W. RSeQC: quality control of RNA-seq experiments. Bioinformatics. 2012;28:2184–5.
Google ScholarÂ
Henning C. Cran-package fpc. https://cran.r-project.org/web/packages/fpc/index.html
Alexa AR, J. topGO: enrichment analysis for Gene Ontology. R package version 1.38.1, 2019.
Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011;27:1739–40.
Google ScholarÂ
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005;102:15545–50.
Google ScholarÂ
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.
Google ScholarÂ
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.
Google ScholarÂ
Amelio I, Tsvetkov PO, Knight RA, Lisitsa A, Melino G, Antonov AV. SynTarget: an online tool to test the synergetic effect of genes on survival outcome in cancer. Cell Death Differ. 2016;23:912.
Google ScholarÂ
Tsalkova T, Mei FC, Li S, Chepurny OG, Leech CA, Liu T, et al. Isoform-specific antagonists of exchange proteins directly activated by cAMP. Proc Natl Acad Sci USA 2012;109:18613–8.
Google ScholarÂ
Almahariq M, Tsalkova T, Mei FC, Chen H, Zhou J, Sastry SK, et al. A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Mol Pharmacol. 2013;83:122–8.
Google ScholarÂ
Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436:720–4.
Google ScholarÂ
Serezani CH, Ballinger MN, Aronoff DM, Peters-Golden M. Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol. 2008;39:127–32.
Google ScholarÂ
Choi E-H, Park S-J. TXNIP: a key protein in the cellular stress response pathway and a potential therapeutic target. Exp Mol Med. 2023;55:1348–56.
Google ScholarÂ
Deng J, Pan T, Liu Z, McCarthy C, Vicencio JM, Cao L, et al. The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control. Br J Cancer. 2023;129:1877–92.
Google ScholarÂ
Masutani H. Thioredoxin-interacting protein in cancer and diabetes. Antioxid Redox Signal. 2022;36:1001–22.
Google ScholarÂ
Nakayama Y, Mukai N, Kreitzer G, Patwari P, Yoshioka J. Interaction of ARRDC4 With GLUT1 mediates metabolic stress in the ischemic heart. Circ Res. 2022;131:510–27.
Google ScholarÂ
Ahn SH, Jang SK, Kim YJ, Kim G, Park KS, Park IC, et al. Amino acid deprivation induces TXNIP expression by NRF2 downregulation. IUBMB Life. 2024;76:212–22.
Google ScholarÂ
Baker AF, Koh MY, Williams RR, James B, Wang H, Tate WR, et al. Identification of thioredoxin-interacting protein 1 as a hypoxia-inducible factor 1alpha-induced gene in pancreatic cancer. Pancreas. 2008;36:178–86.
Google ScholarÂ
Deng J, Pan T, Wang D, Hong Y, Liu Z, Zhou X, et al. The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas. EMBO Mol Med. 2024;16:2080–108.
Google ScholarÂ
Kibbe C, Chen J, Xu G, Jing G, Shalev A. FOXO1 competes with carbohydrate response element-binding protein (ChREBP) and inhibits thioredoxin-interacting protein (TXNIP) transcription in pancreatic beta cells. J Biol Chem. 2013;288:23194–202.
Google ScholarÂ
Pan Q, Ma J, Guo K. miR-223 Enhances the neuroprotection of estradiol against oxidative stress injury by inhibiting the FOXO3/TXNIP axis. Neurochem Res. 2022;47:1865–77.
Google ScholarÂ
Dodd KM, Yang J, Shen MH, Sampson JR, Tee AR. mTORC1 drives HIF-1alpha and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene. 2015;34:2239–50.
Google ScholarÂ
Land SC, Tee AR. Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem. 2007;282:20534–43.
Google ScholarÂ
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.
Google ScholarÂ
Saxena G, Chen J, Shalev A. Intracellular shuttling and mitochondrial function of thioredoxin-interacting protein. J Biol Chem. 2010;285:3997–4005.
Google ScholarÂ
Hong SK, Starenki D, Wu PK, Park JI. Suppression of B-Raf(V600E) melanoma cell survival by targeting mitochondria using triphenyl-phosphonium-conjugated nitroxide or ubiquinone. Cancer Biol Ther. 2017;18:106–14.
Google ScholarÂ
Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, et al. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem. 2003;278:8516–25.
Google ScholarÂ
Mangmool S, Hemplueksa P, Parichatikanond W, Chattipakorn N. Epac is required for GLP-1R-mediated inhibition of oxidative stress and apoptosis in cardiomyocytes. Mol Endocrinol. 2015;29:583–96.
Google ScholarÂ
Hoek KS, Eichhoff OM, Schlegel NC, Dobbeling U, Kobert N, Schaerer L, et al. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res. 2008;68:650–6.
Google ScholarÂ
Baljinnyam E, Umemura M, De Lorenzo MS, Iwatsubo M, Chen S, Goydos JS, et al. Epac1 promotes melanoma metastasis via modification of heparan sulfate. Pigment Cell Melanoma Res. 2011;24:680–7.
Google ScholarÂ
Baljinnyam E, Umemura M, Chuang C, De Lorenzo MS, Iwatsubo M, Chen S, et al. Epac1 increases migration of endothelial cells and melanoma cells via FGF2-mediated paracrine signaling. Pigment Cell Melanoma Res. 2014;27:611–20.
Google ScholarÂ
Grandoch M, Rose A, ter Braak M, Jendrossek V, Rubben H, Fischer JW, et al. Epac inhibits migration and proliferation of human prostate carcinoma cells. Br J Cancer. 2009;101:2038–42.
Google ScholarÂ
Sun DP, Fang CL, Chen HK, Wen KS, Hseu YC, Hung ST, et al. EPAC1 overexpression is a prognostic marker and its inhibition shows promising therapeutic potential for gastric cancer. Oncol Rep. 2017;37:1953–60.
Google ScholarÂ
Kong X, Ai G, Wang D, Chen R, Guo D, Yao Y, et al. PDE4 and Epac1 synergistically promote rectal carcinoma via the cAMP pathway. Anal Cell Pathol. 2019;2019:7145198.
Google ScholarÂ
Huk DJ, Ashtekar A, Magner A, La Perle K, Kirschner LS. Deletion of Rap1b, but not Rap1a or Epac1, reduces protein kinase A-mediated thyroid cancer. Thyroid. 2018;28:1153–61.
Google ScholarÂ
Gao M, Ma Y, Bast RC Jr, Li Y, Wan L, Liu Y, et al. Epac1 knockdown inhibits the proliferation of ovarian cancer cells by inactivating AKT/Cyclin D1/CDK4 pathway in vitro and in vivo. Med Oncol. 2016;33:73.
Google ScholarÂ
Li Z, Liu Q, Cai Y, Ye N, He Z, Yao Y, et al. EPAC inhibitor suppresses angiogenesis and tumor growth of triple-negative breast cancer. Biochim Biophys Acta Mol Basis Dis. 2024;1870:167114.
Google ScholarÂ
Junn E, Han SH, Im JY, Yang Y, Cho EW, Um HD, et al. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol. 2000;164:6287–95.
Google ScholarÂ
Chen Y, Feng X, Yuan Y, Jiang J, Zhang P, Zhang B. Identification of a novel mechanism for reversal of doxorubicin-induced chemotherapy resistance by TXNIP in triple-negative breast cancer via promoting reactive oxygen-mediated DNA damage. Cell Death Dis. 2022;13:338.
Google ScholarÂ
Ji S, Qin Y, Liang C, Huang R, Shi S, Liu J, et al. FBW7 (F-box and WD repeat domain-containing 7) negatively regulates glucose metabolism by targeting the c-Myc/TXNIP (thioredoxin-binding protein) axis in pancreatic cancer. Clin Cancer Res. 2016;22:3950–60.
Google ScholarÂ
Jiao D, Huan Y, Zheng J, Wei M, Zheng G, Han D, et al. UHRF1 promotes renal cell carcinoma progression through epigenetic regulation of TXNIP. Oncogene. 2019;38:5686–99.
Google ScholarÂ
Nishizawa K, Nishiyama H, Matsui Y, Kobayashi T, Saito R, Kotani H, et al. Thioredoxin-interacting protein suppresses bladder carcinogenesis. Carcinogenesis. 2011;32:1459–66.
Google ScholarÂ
Meylan P, Pich C, Winkler C, Ginster S, Mury L, Sgandurra M, et al. Low expression of the PPARgamma-regulated gene thioredoxin-interacting protein accompanies human melanoma progression and promotes experimental lung metastases. Sci Rep. 2021;11:7847.
Google ScholarÂ
Knoll S, Furst K, Kowtharapu B, Schmitz U, Marquardt S, Wolkenhauer O, et al. E2F1 induces miR-224/452 expression to drive EMT through TXNIP downregulation. EMBO Rep. 2014;15:1315–29.
Google ScholarÂ
Talantov D, Mazumder A, Yu JX, Briggs T, Jiang Y, Backus J, et al. Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Res. 2005;11:7234–42.
Google ScholarÂ
Kabbarah O, Nogueira C, Feng B, Nazarian RM, Bosenberg M, Wu M, et al. Integrative genome comparison of primary and metastatic melanomas. PLoS ONE. 2010;5:e10770.
Google ScholarÂ
Ortega-Bernal D, La Rosa CHG, Arechaga-Ocampo E, Alvarez-Avitia MA, Moreno NS, Rangel-Escareno C. A meta-analysis of transcriptome datasets characterizes malignant transformation from melanocytes and nevi to melanoma. Oncol Lett. 2018;16:1899–911.
Google ScholarÂ
Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148:399–408.
Google ScholarÂ
Qannita RA, Alalami AI, Harb AA, Aleidi SM, Taneera J, Abu-Gharbieh E, et al. Targeting hypoxia-inducible factor-1 (HIF-1) in cancer: emerging therapeutic strategies and pathway regulation. Pharmaceuticals. 2024;17:195.
Li Y, Miao LY, Xiao YL, Huang M, Yu M, Meng K, et al. Hypoxia induced high expression of thioredoxin interacting protein (TXNIP) in non-small cell lung cancer and its prognostic effect. Asian Pac J Cancer Prev. 2015;16:2953–8.
Google ScholarÂ
Parmenter TJ, Kleinschmidt M, Kinross KM, Bond ST, Li J, Kaadige MR, et al. Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov. 2014;4:423–33.
Google ScholarÂ
Jandova J, Wondrak GT. Genomic GLO1 deletion modulates TXNIP expression, glucose metabolism, and redox homeostasis while accelerating human A375 malignant melanoma tumor growth. Redox Biol. 2021;39:101838.
Google ScholarÂ
Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell. 2020;38:167–97.
Google ScholarÂ
Hecht F, Zocchi M, Alimohammadi F, Harris IS. Regulation of antioxidants in cancer. Mol Cell. 2024;84:23–33.
Google ScholarÂ
Benhar M, Shytaj IL, Stamler JS, Savarino A. Dual targeting of the thioredoxin and glutathione systems in cancer and HIV. J Clin Investig. 2016;126:1630–9.
Google ScholarÂ
Yang B, Lin Y, Huang Y, Shen YQ, Chen Q. Thioredoxin (Trx): a redox target and modulator of cellular senescence and aging-related diseases. Redox Biol. 2024;70:103032.
Google ScholarÂ
Huang LE, Arany Z, Livingston DM, Bunn HF. Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem. 1996;271:32253–9.
Google ScholarÂ
Tang D, Chen M, Huang X, Zhang G, Zeng L, Zhang G, et al. SRplot: A free online platform for data visualization and graphing. PLoS ONE. 2023;18:e0294236.
Google ScholarÂ
Li J, Miao B, Wang S, Dong W, Xu H, Si C, et al. Hiplot: a comprehensive and easy-to-use web service for boosting publication-ready biomedical data visualization. Brief Bioinform. 2022;23:bbac261.
Semenza GL. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med. 2001;7:345–50.
Google ScholarÂ

