title: Characterization of docosahexaenoic acid (DHA)-induced heme oxygenase-1 (HO-1) expression in human cancer cells: the importance of enhanced BTB and CNC homology 1 (Bach1) degradation.
abstract: The effect of docosahexaenoic acid (DHA) on heme oxygenase-1 (HO-1) expression in cancer cells has never been characterized. This study examines DHA-induced HO-1 expression in human cancer cell model systems. DHA enhanced HO-1 gene expression in a time- and concentration-dependent manner, with maximal induction at 21 h of treatment. This induction of HO-1 expression was confirmed in vivo using a xenograft nude mouse model fed a fish-oil-enriched diet. The increase in HO-1 gene transcription induced by DHA was significantly attenuated by the antioxidant N-acetyl cysteine, suggesting the involvement of oxidative stress. This was supported by direct measurement of lipid peroxide levels after DHA treatment. Using a human HO-1 gene promoter reporter construct, we identified two antioxidant response elements (AREs) that mediate the DHA-induced increase in HO-1 gene transcription. Knockdown of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression compromised the DHA-induced increase in HO-1 gene transcription, indicating the importance of the Nrf2 pathway in this event. However, the nuclear protein levels of Nrf2 remained unchanged upon DHA treatment. Further studies demonstrated that DHA reduces nuclear Bach1 protein expression by promoting its degradation and attenuates Bach1 binding to the AREs in the HO-1 gene promoter. In contrast, DHA enhanced Nrf2 binding to the AREs without affecting nuclear Nrf2 expression levels, indicating a new cellular mechanism that mediates DHA's induction of HO-1 gene transcription. To our knowledge, this is the first characterization of DHA-induced HO-1 expression in human malignant cells.
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 411A, Oklahoma City, OK 73104, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 411A, Oklahoma City, OK 73104, USA.
authors.forename: Bethany N
authors.initials: BN
authors.lastname: Hannafon
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 411A, Oklahoma City, OK 73104, USA.
authors.forename: Roman F
authors.initials: RF
authors.lastname: Wolf
authors.affiliation: Department of Radio-Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, P. R. China.
authors.forename: Jundong
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 411A, Oklahoma City, OK 73104, USA.
authors.forename: Jori E
authors.initials: JE
authors.lastname: Avery
authors.affiliation: Department of Radio-Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, P. R. China.
authors.forename: Jinchang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Departments of Pathology and Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Lind
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 411A, Oklahoma City, OK 73104, USA. Electronic address: weiqun-ding@ouhsc.edu.
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Ding
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000187:drug effects; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D004281:Docosahexaenoic Acids; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: Antioxidant response element; Cancer; Gene transcription regulation; Heme oxygenase-1; n-3 PUFA