title: Activating transcription factor 3-mediated chemo-intervention with cancer chemokines in a noncanonical pathway under endoplasmic reticulum stress.
abstract: The cell-protective features of the endoplasmic reticulum (ER) stress response are chronically activated in vigorously growing malignant tumor cells, which provide cellular growth advantages over the adverse microenvironment including chemotherapy. As an intervention with ER stress responses in the intestinal cancer cells, preventive exposure to flavone apigenin potentiated superinduction of a regulatory transcription factor, activating transcription factor 3 (ATF3), which is also known to be an integral player coordinating ER stress response-related gene expression. ATF3 superinduction was due to increased turnover of ATF3 transcript via stabilization with HuR protein in the cancer cells under ER stress. Moreover, enhanced ATF3 caused inhibitory action against ER stress-induced cancer chemokines that are potent mediators determining the survival and metastatic potential of epithelial cancer cells. Although enhanced ATF3 was a negative regulator of the well known proinflammatory transcription factor NF-κB, blocking of NF-κB signaling did not affect ER stress-induced chemokine expression. Instead, immediately expressed transcription factor early growth response protein 1 (EGR-1) was positively involved in cancer chemokine induction by ER stressors. ER stress-induced EGR-1 and subsequent chemokine production were repressed by ATF3. Mechanistically, ATF3 directly interacted with and recruited HDAC1 protein, which led to epigenetic suppression of EGR-1 expression and subsequent chemokine production. Conclusively, superinduced ATF3 attenuated ER stress-induced cancer chemokine expression by epigenetically interfering with induction of EGR-1, a transcriptional modulator crucial to cancer chemokine production. Thus, these results suggest a potent therapeutic intervention of ER stress response-related cancer-favoring events by ATF3.
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 626-870, Korea,; Research Institute for Basic Sciences and Medical Research Institute, Pusan National University, Busan 609-735, Korea.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Juil
authors.initials: J
authors.lastname: Kim
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Kee Hun
authors.initials: KH
authors.lastname: Do
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Park
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Chang Gyu
authors.initials: CG
authors.lastname: Oh
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Bo Gyoung
authors.initials: BG
authors.lastname: Song
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Medicine, Seoul National University, Seoul 110-799, Korea, and.
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 626-870, Korea,; Research Institute for Basic Sciences and Medical Research Institute, Pusan National University, Busan 609-735, Korea,; Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Busan 609-735, South Korea. Electronic address: moon@pnu.edu.
authors.forename: Yuseok
authors.initials: Y
authors.lastname: Moon
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism; D000067780:ELAV-Like Protein 1; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D044127:Epigenesis, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055550:Protein Stability; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D018925:Chemokines; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C094815:NAB1 protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012097:Repressor Proteins
keywords: ATF3; Apigenin; Cancer Chemoprevention; Chemokine; ER Stress; Early Growth Response Protein 1 (EGR-1); Intestinal Cancer Cells; NF-kB Transcription Factor