The Role of AP-1 in Cancer: Regulation, Tumor Microenvironment and Therapeutic Targeting

The activator protein-1 (AP-1) transcription factor is a regulatory dimeric transcription factor complex, that responds to a wide range of intracellular and extracellular stimuli and controls gene expression involved in tumor initiation and progression. Comprised primarily of members of Jun and Fos protein subfamilies, AP-1 is activated downstream of major oncogenic signaling pathways such as the mitogen-activated protein kinase (MAPK) pathway and controls cellular processes including differentiation, invasion, proliferation and apoptosis. In various cancer types, AP-1 contributes to tumor growth by promoting tumor-like phenotypes and facilitating metastatic behavior. Furthermore, AP-1 can affect the tumor microenvironment by modulating inflammation and interaction with immune cells. AP-1 deregulation is linked to tumor heterogeneity and resistance to chemotherapy and radiation. Therefore, AP-1 has emerged as a potential therapeutic target. In preclinical models, direct and indirect targeting via upstream pathways of AP-1 components has demonstrated encouraging results. In addition, combinatorial approaches targeting AP-1 and other regulators may improve the effectiveness of treatment and overcome therapy resistance. In this review, we highlight the AP-1's role as a critical hub in tumorigenesis that links oncogenic signaling to transcriptional regulation. We also focus on its regulation, function in the tumor microenvironment, and therapeutic potential in combating tumors.