Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells

• Published in: Trends in endocrinology and metabolism Vol. 28; no. 11; pp. 794 - 806
• Main Authors: Wortel, Inge M.N., van der Meer, Laurens T., Kilberg, Michael S., van Leeuwen, Frank N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.11.2017
• Subjects: Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Activating Transcription Factor 4 - physiology; Adaptation, Physiological - genetics; Amino Acids - deficiency; Animals; Apoptosis - genetics; ATF4; Cell Survival - genetics; cellular stress; Humans; Hypoxia - genetics; Hypoxia - metabolism; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; post-translational modification; Protein Processing, Post-Translational; Stress, Physiological - physiology; post-translational modification; ATF4; cellular stress
• ISSN: 1043-2760; 1879-3061
• DOI: 10.1016/j.tem.2017.07.003

Activating transcription factor 4 (ATF4) is a stress-induced transcription factor that is frequently upregulated in cancer cells. ATF4 controls the expression of a wide range of adaptive genes that allow cells to endure periods of stress, such as hypoxia or amino acid limitation. However, under persistent stress conditions, ATF4 promotes the induction of apoptosis. Recent advances point to a role for post-translational modifications (PTMs) and epigenetic mechanisms in balancing these pro- and anti-survival effects of ATF4. We review here how PTMs and epigenetic modifiers associated with ATF4 may be exploited by cancer cells to cope with cellular stress conditions that are intrinsically associated with tumor growth. Identification of mechanisms that modulate ATF4-mediated transcription and its effects on cellular metabolism may uncover new targets for cancer treatment. Mammalian cells utilize sophisticated mechanisms to respond to unfavorable conditions such as nutrient limitation. The transcription factor ATF4 plays a central role in this response. Although activation of ATF4 predominantly serves to promote survival under stress, it can also induce apoptosis. ATF4 signaling supports many normal biological processes, such as the maintenance of stem and progenitor cells or immune regulation, but these functions can be hijacked by cancer cells to sustain rapid tumor growth and survive the hostile tumor microenvironment. How cancer cells selectively exploit the pro-survival effects of ATF4 could relate to changes in PTMs of ATF4 or in ATF4 association with epigenetic modifiers that are specifically altered in cancer cells. Deeper insight into these tumor-associated mechanisms may lead the way to improving therapy responses in cancer patients.