title: ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis.
abstract: The integrated stress response (ISR) is a critical mediator of cancer cell survival, and targeting the ISR inhibits tumor progression. Here, we have shown that activating transcription factor 4 (ATF4), a master transcriptional effector of the ISR, protects transformed cells against anoikis - a specialized form of apoptosis - following matrix detachment and also contributes to tumor metastatic properties. Upon loss of attachment, ATF4 activated a coordinated program of cytoprotective autophagy and antioxidant responses, including induced expression of the major antioxidant enzyme heme oxygenase 1 (HO-1). HO-1 upregulation was the result of simultaneous activation of ATF4 and the transcription factor NRF2, which converged on the HO1 promoter. Increased levels of HO-1 ameliorated oxidative stress and cell death. ATF4-deficient human fibrosarcoma cells were unable to colonize the lungs in a murine model, and reconstitution of ATF4 or HO-1 expression in ATF4-deficient cells blocked anoikis and rescued tumor lung colonization. HO-1 expression was higher in human primary and metastatic tumors compared with noncancerous tissue. Moreover, HO-1 expression correlated with reduced overall survival of patients with lung adenocarcinoma and glioblastoma. These results establish HO-1 as a mediator of ATF4-dependent anoikis resistance and tumor metastasis and suggest ATF4 and HO-1 as potential targets for therapeutic intervention in solid tumors.
authors.forename: Souvik
authors.initials: S
authors.lastname: Dey
authors.forename: Carly M
authors.initials: CM
authors.lastname: Sayers
authors.forename: Ioannis I
authors.initials: II
authors.lastname: Verginadis
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Lehman
authors.forename: Yi
authors.initials: Y
authors.lastname: Cheng
authors.forename: George J
authors.initials: GJ
authors.lastname: Cerniglia
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Tuttle
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.forename: Paul J L
authors.initials: PJ
authors.lastname: Zhang
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
mesh_terms: D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000818:Animals; D023102:Anoikis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004790:Enzyme Induction; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: C497109:ATF4 protein, human; C081452:Atf4 protein, mouse; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D051701:Activating Transcription Factor 4; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse