title: Glutathione S-transferase alpha 4 induction by activator protein 1 in colorectal cancer.
abstract: Glutathione S-transferase alpha 4 (GSTA4) is a phase II detoxifying enzyme that metabolizes electrophiles and carcinogens including 4-hydroxy-2-nonenal (4-HNE), an endogenous carcinogen that contributes to colorectal carcinogenesis. In this study, we investigated GSTA4 expression and regulation in murine primary colonic epithelial cells, microbiome-driven murine colitis and human carcinomas. Exposure of YAMC cells to 4-HNE induced Gsta4 expression. Using an inflammation-associated model of colorectal cancer (CRC), Gsta4 expression increased in vivo in colon macrophages and serum after 2 weeks of colonization of IL-10 deficient (Il10-/-) mice with Enterococcus faecalis. Increased expression was noted after 9 months of colonization in colon macrophages and epithelia in areas of inflammation. In human colon biopsies, immunohistochemistry showed no GSTA4 expression in normal epithelial cells, whereas GSTA4 was strongly expressed in the neoplastic epithelia of invasive carcinomas. For tubular adenomas, increased expression was primarily noted in stromal macrophages. Increased GSTA4 was confirmed in established human CRC cell lines and associated with 4-HNE-protein adducts in human colon adenomas and CRC. Next, we showed that 4-HNE induced activation of c-Jun and Nrf2, two components of the oncogenic transcription factor AP-1. AP-1 inhibitors and gene-specific small interfering RNAs partially suppressed GSTA4 expression. Co-immunoprecipitation confirmed interactions between c-Jun and Nrf2 supporting a role for AP-1 in regulating 4-HNE-induced GSTA4 expression. These findings demonstrate GSTA4 activation during 4-HNE-induced neoplastic transformation in colorectal carcinogenesis. GSTA4 is a potential surrogate biomarker for CRC screening and should provide novel approaches for chemoprevention.
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|The Muchmore Laboratories for Infectious Diseases Research, Oklahoma City VA Health Care System, Oklahoma City, OK, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: The Muchmore Laboratories for Infectious Diseases Research, Oklahoma City VA Health Care System, Oklahoma City, OK, USA.|Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Huycke
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Herman
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|The Muchmore Laboratories for Infectious Diseases Research, Oklahoma City VA Health Care System, Oklahoma City, OK, USA.
authors.forename: X
authors.identifier: 0000-0001-5655-9012
authors.initials: X
authors.lastname: Wang
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004847:Epithelial Cells; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; C027576:4-hydroxy-2-nonenal