Ying H, Kimmelman AC, Bardeesy N, Kalluri R, Maitra A, DePinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2025;39:36–63.
Google Scholar
Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, Maitra A. Pancreatic cancer: advances and challenges. Cell. 2023;186:1729–54.
Google Scholar
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.
Google Scholar
Zhou Q, Melton DA. Pancreas regeneration. Nature. 2018;557:351–8.
Google Scholar
Han H, Von Hoff DD. SnapShot: pancreatic cancer. Cancer Cell. 2013;23:424–424.e1.
Google Scholar
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.
Google Scholar
Eso Y, Shimizu T, Takeda H, Takai A, Marusawa H. Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers. J Gastroenterol. 2020;55:15–26.
Google Scholar
O’Reilly EM, Oh DY, Dhani N, Renouf DJ, Lee MA, Sun W, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5:1431–8.
Google Scholar
Ton CC, Miwa H, Saunders GF. Small eye (Sey): cloning and characterization of the murine homolog of the human aniridia gene. Genomics. 1992;13:251–6.
Google Scholar
Glaser T, Walton DS, Maas RL. Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet. 1992;2:232–9.
Google Scholar
Carriere C, Plaza S, Martin P, Quatannens B, Bailly M, Stehelin D, et al. Characterization of quail Pax-6 (Pax-QNR) proteins expressed in the neuroretina. Mol Cell Biol. 1993;13:7257–66.
Google Scholar
Epstein J, Cai J, Glaser T, Jepeal L, Maas R. Identification of a Pax paired domain recognition sequence and evidence for DNA-dependent conformational changes. J Biol Chem. 1994;269:8355–61.
Google Scholar
Tuoc TC, Stoykova A. Trim11 modulates the function of neurogenic transcription factor Pax6 through ubiquitin-proteosome system. Genes Dev. 2008;22:1972–86.
Google Scholar
Mikkola I, Bruun JA, Bjorkoy G, Holm T, Johansen T. Phosphorylation of the transactivation domain of Pax6 by extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. J Biol Chem. 1999;274:15115–26.
Google Scholar
Kim EA, Noh YT, Ryu MJ, Kim HT, Lee SE, Kim CH, et al. Phosphorylation and transactivation of Pax6 by homeodomain-interacting protein kinase 2. J Biol Chem. 2006;281:7489–97.
Google Scholar
Yan Q, Liu WB, Qin J, Liu J, Chen HG, Huang X, et al. Protein phosphatase-1 modulates the function of Pax-6, a transcription factor controlling brain and eye development. J Biol Chem. 2007;282:13954–65.
Google Scholar
Kleinjan DA, Seawright A, Childs AJ, van Heyningen V. Conserved elements in Pax6 intron 7 involved in (auto)regulation and alternative transcription. Dev Biol. 2004;265:462–77.
Google Scholar
Yan Q, Gong L, Deng M, Zhang L, Sun S, Liu J, et al. Sumoylation activates the transcriptional activity of Pax-6, an important transcription factor for eye and brain development. Proc Natl Acad Sci USA. 2010;107:21034–9.
Google Scholar
Onishi A, Peng GH, Hsu C. Pias3-dependent SUMOylation directs rod photoreceptor development. Neuron. 2009;61:234–46.
Google Scholar
Onishi A, Peng GH, Chen S, Blackshaw S. Pias3-dependent SUMOylation controls mammalian cone photoreceptor differentiation. Nat Neurosci. 2010;13:1059–65.
Google Scholar
Wu DM, Zhang T, Liu YB, Deng SH, Han R, Liu T, et al. The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling. Cell Death Dis. 2019;10:349.
Google Scholar
Ooki A, Dinalankara W, Marchionni L, Tsay JJ, Goparaju C, Maleki Z, et al. Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma. Oncogene. 2018;37:5967–81.
Google Scholar
Zhou YH, Tan F, Hess KR, Yung WK. The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. Clin Cancer Res. 2003;9:3369–75.
Google Scholar
Hao C, Gao C, Shang H, Liu J, Qi F. MicroRNA-31 inhibits the growth and metastasis and enhances drug sensitivity of the human colon cancer cells by targeting PAX6. J BUON. 2020;25:1860–5.
Google Scholar
Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med. 2008;359:918–27.
Google Scholar
Hu B, Wang Q, Wang YA, Hua S, Sauvé CG, Ong D, et al. Epigenetic activation of WNT5A drives glioblastoma stem cell differentiation and invasive growth. Cell. 2016;167:1281–1295.e18.
Google Scholar
Mascarenhas JB, Young KP, Littlejohn EL, Yoo BK, Salgia R, Lang D. PAX6 is expressed in pancreatic cancer and actively participates in cancer progression through activation of the MET tyrosine kinase receptor gene. J Biol Chem. 2009;284:27524–32.
Google Scholar
Lang D, Mascarenhas JB, Powell SK, Halegoua J, Nelson M, Ruggeri BA. PAX6 is expressed in pancreatic adenocarcinoma and is downregulated during induction of terminal differentiation. Mol Carcinog. 2008;47:148–56.
Google Scholar
Geiss-Friedlander R, Melchior F. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol. 2007;8:947–56.
Google Scholar
Flotho A, Melchior F. Sumoylation: a regulatory protein modification in health and disease. Annu Rev Biochem. 2013;82:357–85.
Google Scholar
Du L, Liu W, Rosen ST. Targeting SUMOylation in cancer. Curr Opin Oncol. 2021;33:520–5.
Google Scholar
Kroonen JS, Vertegaal ACO. Targeting SUMO signaling to wrestle cancer. Trends Cancer. 2021;7:496–510.
Google Scholar
Tiwari PK. Epigenetic biomarkers in gallbladder cancer. Trends Cancer. 2020;6:540–3.
Google Scholar
Rabellino A, Andreani C, Scaglioni PP. The role of PIAS SUMO E3-ligases in cancer. Cancer Res. 2017;77:1542–7.
Google Scholar
Seeler JS, Dejean A. SUMO and the robustness of cancer. Nat Rev Cancer. 2017;17:184–97.
Google Scholar
Eifler K, Vertegaal ACO. SUMOylation-mediated regulation of cell cycle progression and cancer. Trends Biochem Sci. 2015;40:779–93.
Google Scholar
Bogachek MV, Chen Y, Kulak MV, Woodfield GW, Cyr AR, Park JM, et al. Sumoylation pathway is required to maintain the basal breast cancer subtype. Cancer Cell. 2014;25:748–61.
Google Scholar
Miyazono K, Kamiya Y, Miyazawa K. SUMO amplifies TGF-beta signalling. Nat Cell Biol. 2008;10:635–7.
Google Scholar
Yu F, Zhang W, Yan C, Yan D, Zhou M, Chen J, et al. PAX6, modified by SUMOylation, plays a protective role in corneal endothelial injury. Cell Death Dis. 2020;11:683.
Google Scholar
Li P, Ge D, Li P, Hu F, Chu J, Chen X, et al. CXXC finger protein 4 inhibits the CDK18-ERK1/2 axis to suppress the immune escape of gastric cancer cells with involvement of ELK1/MIR100HG pathway. J Cell Mol Med. 2020;24:10151–65.
Google Scholar
Lu H, Sun J, Wang F, Feng L, Ma Y, Shen, Q, et al. Enhancer of zeste homolog 2 activates WNT signaling through downregulating CXXC finger protein 4. Cell Death Dis. 2013;4:e776.
Google Scholar
Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004;5:691–701.
Google Scholar
He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in WNT/beta-catenin signaling: arrows point the way. Development. 2004;131:1663–77.
Google Scholar
MacDonald BT, Tamai K, He X. WNT/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.
Google Scholar
Lu H, Jin W, Sun J, Feng L, Lan H, Shen Q, et al. New tumor suppressor CXXC finger protein 4 inactivates mitogen activated protein kinase signaling. FEBS Lett. 2014;588:3322–6.
Google Scholar
Di C, Liang J, Wang Y, Zhao G, Zhao Y. SPZ1 promotes glioma aggravation via targeting CXXC4. J BUON. 2021;26:373–9.
Google Scholar
Lu J, Lu S, Li J, Yu Q, Liu L, Li Q. MiR-629-5p promotes colorectal cancer progression through targetting CXXC finger protein 4. Biosci Rep. 2018;38:BSR20180613.
Google Scholar
Liu S, Qiu J, He G, Geng C, He W, Liu C, et al. Dermatopontin inhibits WNT signaling pathway via CXXC finger protein 4 in hepatocellular carcinoma. J Cancer. 2020;11:6288–98.
Google Scholar
Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, et al. BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov. 2021;11:142–57.
Google Scholar
Fu JL, Zheng SY, Wang Y, Hu XB, Xiao Y, Wang JM, et al. HSP90β prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53. Proc Natl Acad Sci USA. 2023;120:e2221522120.
Google Scholar
Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med. 1999;341:1715–24.
Google Scholar
Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8:663–72.
Google Scholar
Liu FY, Fu JL, Wang L, Nie Q, Luo Z, Hou M, et al. Molecular signature for senile and complicated cataracts derived from analysis of sumoylation enzymes and their substrates in human cataract lenses. Aging Cell. 2020;19:e13222.
Google Scholar
Gong L, Liu F, Xiong Z, Qi R, Luo Z, Gong X, et al. Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes. Proc Natl Acad Sci USA. 2018;115:E3987–E3995.
Google Scholar
Carter S, Bischof O, Dejean A, Vousden KH. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol. 2007;9:428–35.
Google Scholar
Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer. 2004;4:793–805.
Google Scholar
Morris JR, Boutell C, Keppler M, Densham R, Weekes D, Alamshah A, et al. The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature. 2009;462:886–90.
Google Scholar
Smolen GA, Vassileva MT, Wells J, Matunis MJ, Haber DA. SUMO-1 modification of the Wilms’ tumor suppressor WT1. Cancer Res. 2004;64:7846–51.
Google Scholar
Kracklauer MP, Schmidt C. At the crossroads of SUMO and NF-kappaB. Mol Cancer. 2003;2:39.
Google Scholar
Janssens S, Tinel A, Lippens S, Tschopp J. PIDD mediates NF-kappaB activation in response to DNA damage. Cell. 2005;123:1079–92.
Google Scholar
Mulero MC, Ferres-Marco D, Islam A, Margalef P, Pecoraro M, Toll A, et al. Chromatin-bound IκBα regulates a subset of polycomb target genes in differentiation and cancer. Cancer Cell. 2013;24:151–66.
Google Scholar
Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, Schmitt EM, et al. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 2012;335:348–53.
Google Scholar
Cheng J, Kang X, Zhang S, Yeh ET. SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell. 2007;131:584–95.
Google Scholar
Wu YC, Ling TY, Lu SH, Kuo HC, Ho HN, Yeh SD, et al. Chemotherapeutic sensitivity of testicular germ cell tumors under hypoxic conditions is negatively regulated by SENP1-controlled sumoylation of OCT4. Cancer Res. 2012;72:4963–73.
Google Scholar
Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science. 2010;328:240–3.
Google Scholar
Jeanne M, Lallemand-Breitenbach V, Ferhi O, Koken M, Le Bras M, Duffort S, et al. PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell. 2010;18:88–98.
Google Scholar
Rabellino A, Carter B, Konstantinidou G, Wu SY, Rimessi A, Byers LA, et al. The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. Cancer Res. 2012;72:2275–84.
Google Scholar
Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008;10:538–46.
Google Scholar
Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, et al. Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol. 2008;10:547–55.
Google Scholar
Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K, et al. Corrigendum: a SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2016;531:126.
Google Scholar
Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480:99–103.
Google Scholar
Luo Y, Li Z, Kong Y, He W, Zheng H, An M, et al. KRAS mutant-driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer. J Clin Investig. 2022;132:e157644.
Google Scholar
Kumar S, Schoonderwoerd MJA, Kroonen JS, de Graaf IJ, Sluijter M, Ruano D, et al. Targeting pancreatic cancer by TAK-981: a SUMOylation inhibitor that activates the immune system and blocks cancer cell cycle progression in a preclinical model. Gut. 2022;71:2266–83.
Google Scholar
Rauth S, Karmakar S, Shah A, Seshacharyulu P, Nimmakayala RK, Ganguly K, et al. SUMO modification of PAF1/PD2 enables PML interaction and promotes radiation resistance in pancreatic ductal adenocarcinoma. Mol Cell Biol. 2021;41:e0013521.
Google Scholar
Arnold F, Gout J, Wiese H, Weissinger SE, Roger E, Perkhofer L, et al. RINT1 regulates SUMOylation and the DNA damage response to preserve cellular homeostasis in pancreatic cancer. Cancer Res. 2021;81:1758–74.
Google Scholar
Bonacci T, Audebert S, Camoin L, Baudelet E, Bidaut G, Garcia M, et al. Identification of new mechanisms of cellular response to chemotherapy by tracking changes in post-translational modifications by ubiquitin and ubiquitin-like proteins. J Proteome Res. 2014;13:2478–94.
Google Scholar
Biederstädt A, Hassan Z, Schneeweis C, Schick M, Schneider L, Muckenhuber A, et al. SUMO pathway inhibition targets an aggressive pancreatic cancer subtype. Gut. 2020;69:1472–82.
Google Scholar
Deer EL, Gonzalez-Hernandez J, Coursen JD, Shea JE, Ngatia J, Scaife CL, et al. Mulvihill SJ. Phenotype and genotype of pancreatic cancer cell lines. Pancreas. 2010;39:425–35.
Google Scholar
Kyriazis AP, Kyriazis AA, Scarpelli DG, Fogh J, Rao MS, Lepera R. Human pancreatic adenocarcinoma line Capan-1 in tissue culture and the nude mouse: morphologic, biologic, and biochemical characteristics. Am J Pathol. 1982;106:250–60.
Google Scholar
Lieber M, Mazzetta J, Nelson-Rees W, Kaplan M, Todaro G. Establishment of a continuous tumor-cell line (panc-1) from a human carcinoma of the exocrine pancreas. Int J Cancer. 1975;15:741–7.
Google Scholar
Kyriazis AA, Kyriazis AP, Sternberg CN, Sloane NH, Loveless JD. Morphological, biological, biochemical, and karyotypic characteristics of human pancreatic ductal adenocarcinoma Capan-2 in tissue culture and the nude mouse. Cancer Res. 1986;46:5810–5.
Google Scholar
Gulay KCM, Zhang X, Pantazopoulou V, Patel J, Esparza E, Pran Babu DS, et al. Dual inhibition of KRASG12D and Pan-ERBB is synergistic in pancreatic ductal adenocarcinoma. Cancer Res. 2023;83:3001–12.
Google Scholar
Garg B, Khan S, Courelli AS, Panneerpandian P, Sheik Pran Babu D, Mose ES, et al. MICAL2 promotes pancreatic cancer growth and metastasis. Cancer Res. 2025;85:1049–63.
Google Scholar
Antonucci L, Li N, Duran A, Cobo I, Nicoletti C, Watari K, et al. Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer. Nat Cancer. 2025;6:1263–82.
Google Scholar
Mao YW, Liu JP, Xiang H, Li DW. Human alphaA- and alphaB-crystallins bind to Bax and Bcl-X(S) to sequester their translocation during staurosporine-induced apoptosis. Cell Death Differ. 2004;11:512–26.
Google Scholar
Xiao L, Gong LL, Yuan D, Deng M, Zeng XM, Chen LL, et al. Protein phosphatase-1 regulates Akt1signal transduction pathway to control gene expression, cell survival and differentiation. Cell Death Differ. 2010;17:1448–62.
Google Scholar
Zou M, Ke Q, Nie Q, Qi R, Zhu X, Liu W, et al. Inhibition of cGAS-STING by JQ1 alleviates oxidative stress-induced retina inflammation and degeneration. Cell Death Differ. 2022;29:1816–33.
Google Scholar
Qin J, Chen HG, Yan Q, Deng M, Liu J, Doerge S, et al. Protein phosphatase-2A is a target of epigallocatechin-3-gallate and modulates p53-Bak apoptotic pathway. Cancer Res. 2008;68:4150–62.
Google Scholar

