The nuclear oncoprotein Fra-1: a transcription factor knocking on therapeutic applications’ door

• Published in: Oncogene 2020-06, Vol.39 (23), p.4491-4506
• Main Authors: Talotta, Francesco, Casalino, Laura, Verde, Pasquale
• Format: Article
• Language: English
• Subjects: 631/67/395; 631/80; Activator protein 1; Addictions; Animal models; Animals; Apoptosis; Cell Biology; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Development and progression; Disease Models, Animal; Epigenetic inheritance; Epigenetics; Epithelial-Mesenchymal Transition - genetics; Fra1 protein; Gene Expression Regulation, Neoplastic - genetics; Health aspects; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mice; MicroRNAs - genetics; Neoplasm Metastasis - pathology; Neoplasms - genetics; Neoplasms - pathology; Oncology; Oncoproteins; p53 Protein; Protein Processing, Post-Translational - genetics; Proto-Oncogene Proteins c-fos - genetics; Review Article; Solid tumors; Therapeutic applications; Transcription factors; Tumor microenvironment; Tumor Microenvironment - genetics; Tumor proteins; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1306-4

Among the FOS -related members of the AP-1 dimeric complex, the transcription factor Fra-1, encoded by FOSL1 , is crucially involved in human tumor progression and metastasis, thus representing a promising therapeutic target. Here we review the state of the art and discuss the emerging topics and perspectives on FOSL1 and its gene product. First, we summarize the present knowledge on the FOSL1 transcriptional and epigenetic controls, driving Fra-1 accumulation in a variety of human solid tumors. We also present a model on the regulatory interactions between Fra-1, p53, and miRNAs. Then, we outline the multiple roles of Fra-1 posttranslational modifications and transactivation mechanisms of select Fra-1 target genes. In addition to summarizing the Fra-1-dependent gene networks controlling proliferation, survival, and epithelial–mesenchymal transitions (EMT) in multiple cancer cell types, we highlight the roles played by Fra-1 in nonneoplastic cell populations recruited to the tumor microenvironment, and in mouse models of tumorigenesis. Next, we review the prognostic power of the Fra-1-associated gene signatures, and envisage potential strategies aimed at Fra-1 therapeutic inhibition. Finally, we discuss several recent reports showing the emerging roles of Fra-1 in the mechanisms of both resistance and addiction to targeted therapies.