Journal Article

ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis

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

2015

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Activating Transcription Factor 4 - antagonists & inhibitors / Activating Transcription Factor 4 - genetics / Activating Transcription Factor 4 - metabolism / Adenocarcinoma - enzymology / Adenocarcinoma - genetics / Adenocarcinoma of Lung / Animals / Anoikis - genetics / Anoikis - physiology / Biomedical research / Cancer / Cell Line, Tumor / Cell Movement / Colleges & universities / Enzyme Induction / Female / Gene Expression Regulation, Enzymologic / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Glioblastoma - enzymology / Glioblastoma - genetics / Heme Oxygenase-1 - biosynthesis / Heme Oxygenase-1 - genetics / Heterografts / Humans / Hypoxia / Kinases / Lung Neoplasms - enzymology / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Lung Neoplasms - secondary / Lungs / Membrane Proteins - biosynthesis / Membrane Proteins - genetics / Metastasis / Mice / Mice, Nude / Neoplasm Invasiveness / Neoplasm Metastasis - genetics / Neoplasm Metastasis - pathology / Neoplasm Metastasis - physiopathology / NF-E2-Related Factor 2 - antagonists & inhibitors / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - metabolism / Oxidative Stress / Phosphorylation / Reactive Oxygen Species - metabolism / Rodents / Stress response / Transcription factors / Tumors / Unfolded Protein Response