{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:59:44Z","timestamp":1792789184364,"version":"4.5.0"},"reference-count":60,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["K99.R00DK133804"],"award-info":[{"award-number":["K99.R00DK133804"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"award":["K99.R00DK133804"],"award-info":[{"award-number":["K99.R00DK133804"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"name":"University of Colorado Cancer Center","id":[{"id":"https:\/\/ror.org\/04cqn7d42","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04cqn7d42","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Katy O. and Paul M. Rady Esophageal and Gastric Center of Excellence","id":[{"id":"https:\/\/ror.org\/02y9qjz38","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Paul R. O\u2019Hara II Seed Grant, University of Colorado Cancer Center Anschutz Medical Campus, Aurora, Colorado","id":[{"id":"https:\/\/ror.org\/04cqn7d42","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04cqn7d42","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Thomas Charles M. Esophageal Cancer Endowed Research Fund","award":["R01 CA215596"],"award-info":[{"award-number":["R01 CA215596"]}]},{"name":"Thomas Charles M. Esophageal Cancer Endowed Research Fund","award":["P50 CA269022"],"award-info":[{"award-number":["P50 CA269022"]}]},{"name":"Thomas Charles M. Esophageal Cancer Endowed Research Fund","award":["G002823"],"award-info":[{"award-number":["G002823"]}]},{"name":"Thoracic Surgery Foundation STS Award","id":[{"id":"https:\/\/ror.org\/0009jge67","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/0009jge67","id-type":"ROR","asserted-by":"publisher"}]},{"name":"American Association for Thoracic Surgery Surgical Investigator Award","id":[{"id":"https:\/\/ror.org\/048f8az88","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/048f8az88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Glutathione S-transferase theta 2 (GSTT2) is highly expressed in esophageal tissues from African American (AA) compared with European American (EA) individuals, but its localization, regulation, and relevance to esophageal adenocarcinoma progression remain unclear. Methods: Here, we combined FISH, immunofluorescence, patient-derived culture models, cell-cycle synchronization, biochemical perturbation, and transcriptomics to define GSTT2 expression in normal and neoplastic esophageal contexts. Results: In developing and adult esophageal tissues, GSTT2 mRNA and protein were broadly distributed across squamous epithelium and lamina propria, co-localizing with p63-positive basal\/progenitor cells and extending into differentiated compartments, with no major ancestry-associated differences in spatial patterning. In Barrett\u2019s esophagus, GSTT2 protein was retained in metaplastic columnar epithelium and slightly elevated in dysplastic versus adjacent non-dysplastic regions. GSTT2 mRNA was highest in normal squamous esophagus, reduced during Barrett\u2019s-to-adenocarcinoma progression, but increased in treatment-resistant esophageal adenocarcinoma (EAC). In resistant EAC, GSTT2 co-expression shifted from homeostatic antioxidant programs to proliferation and mitotic pathways, including the G2-M checkpoint, E2F targets, and Reactome Cell Cycle, with leading-edge regulators CDK1 and CDC20. Sequence analysis identified putative APC-C and FBXW7 recognition motifs. In synchronized cells, GSTT2 abundance declined during S-G2\/M and increased during mitotic exit\/early G1 in cytosolic and membrane fractions. Forskolin, a dual inhibitor of FBXW7 and CDC20, stabilized GSTT2 and rescued CDC20- or FBXW7-associated loss, implicating APC-CDC20 and FBXW7 pathways in GSTT2 turnover. In EAC cells, by contrast, CDC20 was found to be a cooperative partner stabilizing GSTT2. Conclusions: These findings identify GSTT2 as a spatially widespread, ancestry-associated, cell-cycle-regulated protein with potential oncogenic roles in EAC resistance.<\/jats:p>","DOI":"10.3390\/cancers18193220","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:46:29Z","timestamp":1791283589000},"page":"3220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GSTT2 Switches from a Homeostatic Antioxidant to a Cell-Cycle-Coupled Factor in Therapy-Resistant Esophageal Adenocarcinoma"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3576-0347","authenticated-orcid":false,"given":"Daysha","family":"Ferrer-Torres","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology & Hepatology, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Katy O. and Paul M. Rady Esophageal and Gastric Center of Excellence, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Paramita","family":"Ray","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7487-1552","authenticated-orcid":false,"given":"Noah","family":"Etzioni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology & Hepatology, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Max A.","family":"Hammer","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8756-2820","authenticated-orcid":false,"given":"Archismaan","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Meilan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3662-8815","authenticated-orcid":false,"given":"Vinay","family":"Jeeyar","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Sachin","family":"Wani","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology & Hepatology, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Katy O. and Paul M. Rady Esophageal and Gastric Center of Excellence, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3871-5112","authenticated-orcid":false,"given":"Sunnie S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Katy O. and Paul M. Rady Esophageal and Gastric Center of Excellence, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Department of Oncology, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1319-7653","authenticated-orcid":false,"given":"Benedetto","family":"Mungo","sequence":"additional","affiliation":[{"name":"Katy O. and Paul M. Rady Esophageal and Gastric Center of Excellence, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Department of Surgery, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"given":"Stefan","family":"Marasligiller","sequence":"additional","affiliation":[{"name":"Katy O. and Paul M. Rady Esophageal and Gastric Center of Excellence, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Department of Surgery, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1010-819X","authenticated-orcid":false,"given":"Danielle Kim","family":"Turgeon","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4733-0659","authenticated-orcid":false,"given":"Jules","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"given":"Peter D. R.","family":"Higgins","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.","family":"Spence","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Kiran H.","family":"Lagisetty","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"David G.","family":"Beer","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1297-2312","authenticated-orcid":false,"given":"Dipankar","family":"Ray","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1053\/j.gastro.2022.05.054","article-title":"The Global Landscape of Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma Incidence and Mortality in 2020 and Projections to 2040: New Estimates From GLOBOCAN 2020","volume":"163","author":"Morgan","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.21037\/jgo-22-729","article-title":"A glimpse into the future of esophageal carcinoma in the United States: Predicting the future incidence until 2040 based on the current epidemiological data","volume":"14","author":"Tella","year":"2023","journal-title":"J. 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