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

Oncogene volume 39, pages 4491–4506 (2020)Cite this article

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Abstract

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.

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Fig. 1: Transcriptional regulation of FOSL1.
Fig. 2: Model showing the dual Fra-1 regulation in response to p53.
Fig. 3: Fra-1 posttranslational modifications and DNA-binding sites.
Fig. 4: Roles of Fra-1 in heterotypic interactions with TAMs and CAFs in tumor microenvironment.
Fig. 5: Fra-1 roles in drug-resilience, drug-resistance, and drug-addiction mechanisms.

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Acknowledgements

We wish to thank all the authors whose work was not cited here owing to page limitation. We thank the former members of the lab for fruitful discussions, along with Valerio Costa and Ingram Iaccarino for critical feedback on the paper. We also thank the Regione Campania Project POR-SATIN for financial support.

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  1. Francesco Talotta

    Present address: ReiThera Srl, Castel Romano, Rome, Italy

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  1. Institute of Genetics and Biophysics “Adriano Buzzati Traverso” CNR, Naples, Italy

    Francesco Talotta, Laura Casalino & Pasquale Verde

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  1. Francesco Talotta
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  2. Laura Casalino
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  3. Pasquale Verde
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Correspondence to Pasquale Verde.

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Talotta, F., Casalino, L. & Verde, P. The nuclear oncoprotein Fra-1: a transcription factor knocking on therapeutic applications’ door. Oncogene 39, 4491–4506 (2020). https://doi.org/10.1038/s41388-020-1306-4

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