ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis
Souvik Dey, … , J. Alan Diehl, Constantinos Koumenis
Souvik Dey, … , J. Alan Diehl, Constantinos Koumenis
Published July 1, 2015; First published May 26, 2015
Citation Information: J Clin Invest. 2015;125(7):2592-2608. https://doi.org/10.1172/JCI78031.
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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 7

High HO-1 expression correlates with metastasis and reduced overall survival in patients.

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High HO-1 expression correlates with metastasis and reduced overall surv...
(A) Probability of overall survival in 1406 patients with lung cancer stratified on low (black) versus high (red) expression levels of HO-1 were obtained from Kaplan-Meier Plotter/lung cancer (http://www.kmplot.com/lung). (B) Probability of overall survival in glioblastoma patients with either upregulated (≥2-fold over the mean), downregulated (≤2-fold over the mean), or intermediate HO1 expression is from the Georgetown Database of Cancer (G-DOC Plus) (https://gdoc.georgetown.edu/gdoc/), with n representing the patient number for each group. Statistical significance was calculated based on log-rank test. (C) Immunohistochemical analysis of serial lung sections from mice injected with shNT.HT1080 cells using antibodies against ATF4, HO-1, and LC3. Insets show areas of colocalization in the 3 detected proteins. D and E show expression of HO-1 and ATF4 from surgical specimens from primary breast tumor with known involvement of lymph node metastasis (D) and brain metastatic lesion from a patient with a primary sarcoma (E). T, tumor region; N, normal tissue. Original magnification, ×2, ×5 (insets) (C); ×2, ×4 (insets) (D and E).