ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis
Souvik Dey, Carly M. Sayers, Ioannis I. Verginadis, Stacey L. Lehman, Yi Cheng, George J. Cerniglia, Stephen W. Tuttle, Michael D. Feldman, Paul J.L. Zhang, Serge Y. Fuchs, J. Alan Diehl, Constantinos Koumenis
Souvik Dey, Carly M. Sayers, Ioannis I. Verginadis, Stacey L. Lehman, Yi Cheng, George J. Cerniglia, Stephen W. Tuttle, Michael D. Feldman, Paul J.L. Zhang, Serge Y. Fuchs, J. Alan Diehl, Constantinos Koumenis
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Research Article Oncology

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

Souvik Dey, Carly M. Sayers, Ioannis I. Verginadis, Stacey L. Lehman, Yi Cheng, George J. Cerniglia, Stephen W. Tuttle, Michael D. Feldman, Paul J.L. Zhang, Serge Y. Fuchs, J. Alan Diehl, Constantinos Koumenis

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Figure 8

Model for involvement of HO-1 in ATF4-mediated metastasis.

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Model for involvement of HO-1 in ATF4-mediated metastasis. Detachment of...
Detachment of tumor cells from ECM results in activation of the PERK pathway (and likely the IRE1 and ATF6 pathways), which are normally kept inactive by the endoplasmic reticulum–resident chaperone protein GRP78 (for clarity, only the PERK pathway, which is the focus of this work, is shown here). Activation of PERK mediates eIF2α phosphorylation and translational upregulation of ATF4. In turn, ATF4 activates a cytoprotective autophagy program by upregulating key autophagy genes. ATF4 also cooperates with NRF2 (directly activated by PERK) to activate the antioxidant protein HO-1 to counter increasing oxidative stress following loss of ECM. The combined action of the autophagic and antioxidant effector pathways of the PERK arm of the UPR enables tumor cells to survive longer in circulation and results in increased rates of formation of secondary metastatic sites.