GSTT2 Switches from a Homeostatic Antioxidant to a Cell-Cycle-Coupled Factor in Therapy-Resistant Esophageal Adenocarcinoma.
7 affiliations
- 1Department of Medicine, Division of Gastroenterology & Hepatology, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA.
- 2Katy O. and Paul M. Rady Esophageal and Gastric Center of Excellence, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA.
- 3Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
- 4Department of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA.
- 5Department of Oncology, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA.
- 6Department of Surgery, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO 80045, USA.
- 7Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Abstract
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's 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's-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.
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BibTeX
@article{ferrertorres2026gstt2,
title = {{GSTT2 Switches from a Homeostatic Antioxidant to a Cell-Cycle-Coupled Factor in Therapy-Resistant Esophageal Adenocarcinoma.}},
author = {Daysha Ferrer-Torres and Paramita Ray and Noah Etzioni and Max A Hammer and Archismaan Ghosh and Meilan Liu and Vinay Jeeyar and Sachin Wani and Sunnie S Kim and Benedetto Mungo and Stefan Marasligiller and Danielle Kim Turgeon and Jules Lin and Peter D R Higgins and Jason R Spence and Kiran H Lagisetty and David G Beer and Dipankar Ray},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18193220},
url = {https://europepmc.org/article/MED/42882914},
note = {CC BY},
}
RIS
TY - JOUR
TI - GSTT2 Switches from a Homeostatic Antioxidant to a Cell-Cycle-Coupled Factor in Therapy-Resistant Esophageal Adenocarcinoma.
AU - Daysha Ferrer-Torres
AU - Paramita Ray
AU - Noah Etzioni
AU - Max A Hammer
AU - Archismaan Ghosh
AU - Meilan Liu
AU - Vinay Jeeyar
AU - Sachin Wani
AU - Sunnie S Kim
AU - Benedetto Mungo
AU - Stefan Marasligiller
AU - Danielle Kim Turgeon
AU - Jules Lin
AU - Peter D R Higgins
AU - Jason R Spence
AU - Kiran H Lagisetty
AU - David G Beer
AU - Dipankar Ray
PY - 2026
DA - 2026/10/06
JO - Cancers
DO - 10.3390/cancers18193220
UR - https://europepmc.org/article/MED/42882914
AB - 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's 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's-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.
SN - 2072-6694
ER -