The landscape of ATF3 in tumors: Metabolism, expression regulation, therapy approach, and open concerns

Abstract

Cellular stress response is a pivotal process in tumor development and therapy. Activating transcription factor 3 (ATF3), a representative stress-responsive protein, plays pleiotropic roles in various biological processes. Over the past decade, studies have described not only the general role of ATF3 in tumor metabolism but also the complexity of ATF3 expression regulation and its associated modifications, including phosphorylation, ubiquitination, SUMOylation, and NEDDylation. Interestingly, beyond being a transcription factor, ATF3 can act as a modifier to control the ubiquitination of target molecules, such as p53, to exert its function in tumors. These advances in uncovering ATF3 biological function have yielded new insights into the cellular stress response during tumor development and will be instrumental in developing novel interventions. In this review, we update the role of ATF3 as a nexus in amino acid metabolism, lipid metabolism, glycometabolism, and other metabolic pathways in tumors; delineate the underlying mechanisms involving DNA level regulation, epigenetic regulation, and post-translational modifications of ATF3; and summarize the progression of tumor mono/combination therapies related to ATF3. In particular, we discuss the challenges that need to be addressed to provide a new conceptual framework for further understanding the potential therapeutic value of ATF3 in ongoing clinical trials.