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The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting
SIMPLE SUMMARY: Cancer-associated mortality largely depends on metastatic dissemination. Metastasizing cancer cells exhibit drastic phenotypic changes, including the ability to migrate, invade surrounding tissues, survive in the bloodstream, adapt to different microenvironments, and resist to therap...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946526/ https://www.ncbi.nlm.nih.gov/pubmed/35326630 http://dx.doi.org/10.3390/cancers14061480 |
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author | Casalino, Laura Talotta, Francesco Cimmino, Amelia Verde, Pasquale |
author_facet | Casalino, Laura Talotta, Francesco Cimmino, Amelia Verde, Pasquale |
author_sort | Casalino, Laura |
collection | PubMed |
description | SIMPLE SUMMARY: Cancer-associated mortality largely depends on metastatic dissemination. Metastasizing cancer cells exhibit drastic phenotypic changes, including the ability to migrate, invade surrounding tissues, survive in the bloodstream, adapt to different microenvironments, and resist to therapeutic treatments. These changes depend on the genetic reprogramming orchestrated by relatively few players (transcription factors). Among the components of the dimeric transcription factor AP-1, the nuclear oncoprotein Fra-1 is strongly implicated in metastasis mechanisms. Therefore, Fra-1, along with other proinvasive transcription factors, represents an ideal therapeutic target. However, as for other DNA-binding proteins, the design of inhibitory drugs is hampered by the structural features of Fra-1. In this Review, after summarizing the Fra-1 functions and mechanisms of accumulation in invasive tumors, we survey the possible application of multiple strategies and emerging technologies aimed at the inhibition of Fra-1 expression and activity, to prevent metastatic dissemination and therapeutic resistance. ABSTRACT: The genetic and epigenetic changes affecting transcription factors, coactivators, and chromatin modifiers are key determinants of the hallmarks of cancer. The acquired dependence on oncogenic transcriptional regulators, representing a major determinant of cancer cell vulnerability, points to transcription factors as ideal therapeutic targets. However, given the unavailability of catalytic activities or binding pockets for small-molecule inhibitors, transcription factors are generally regarded as undruggable proteins. Among components of the AP-1 complex, the FOS-family transcription factor Fra-1, encoded by FOSL1, has emerged as a prominent therapeutic target. Fra-1 is overexpressed in most solid tumors, in response to the BRAF-MAPK, Wnt-beta-catenin, Hippo-YAP, IL-6-Stat3, and other major oncogenic pathways. In vitro functional analyses, validated in onco-mouse models and corroborated by prognostic correlations, show that Fra-1-containing dimers control tumor growth and disease progression. Fra-1 participates in key mechanisms of cancer cell invasion, Epithelial-to-Mesenchymal Transition, and metastatic spreading, by driving the expression of EMT-inducing transcription factors, cytokines, and microRNAs. Here we survey various strategies aimed at inhibiting tumor growth, metastatic dissemination, and drug resistance by interfering with Fra-1 expression, stability, and transcriptional activity. We summarize several tools aimed at the design and tumor-specific delivery of Fra-1/AP-1-specific drugs. Along with RNA-based therapeutics targeting the FOSL1 gene, its mRNA, or cognate regulatory circRNAs, we will examine the exploitation of blocking peptides, small molecule inhibitors, and innovative Fra-1 protein degraders. We also consider the possible caveats concerning Fra-1 inhibition in specific therapeutic contexts. Finally, we discuss a recent suicide gene therapy-based approach, aimed at selectively killing the Fra-1-overexpressing neoplastic cells. |
format | Online Article Text |
id | pubmed-8946526 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89465262022-03-25 The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting Casalino, Laura Talotta, Francesco Cimmino, Amelia Verde, Pasquale Cancers (Basel) Review SIMPLE SUMMARY: Cancer-associated mortality largely depends on metastatic dissemination. Metastasizing cancer cells exhibit drastic phenotypic changes, including the ability to migrate, invade surrounding tissues, survive in the bloodstream, adapt to different microenvironments, and resist to therapeutic treatments. These changes depend on the genetic reprogramming orchestrated by relatively few players (transcription factors). Among the components of the dimeric transcription factor AP-1, the nuclear oncoprotein Fra-1 is strongly implicated in metastasis mechanisms. Therefore, Fra-1, along with other proinvasive transcription factors, represents an ideal therapeutic target. However, as for other DNA-binding proteins, the design of inhibitory drugs is hampered by the structural features of Fra-1. In this Review, after summarizing the Fra-1 functions and mechanisms of accumulation in invasive tumors, we survey the possible application of multiple strategies and emerging technologies aimed at the inhibition of Fra-1 expression and activity, to prevent metastatic dissemination and therapeutic resistance. ABSTRACT: The genetic and epigenetic changes affecting transcription factors, coactivators, and chromatin modifiers are key determinants of the hallmarks of cancer. The acquired dependence on oncogenic transcriptional regulators, representing a major determinant of cancer cell vulnerability, points to transcription factors as ideal therapeutic targets. However, given the unavailability of catalytic activities or binding pockets for small-molecule inhibitors, transcription factors are generally regarded as undruggable proteins. Among components of the AP-1 complex, the FOS-family transcription factor Fra-1, encoded by FOSL1, has emerged as a prominent therapeutic target. Fra-1 is overexpressed in most solid tumors, in response to the BRAF-MAPK, Wnt-beta-catenin, Hippo-YAP, IL-6-Stat3, and other major oncogenic pathways. In vitro functional analyses, validated in onco-mouse models and corroborated by prognostic correlations, show that Fra-1-containing dimers control tumor growth and disease progression. Fra-1 participates in key mechanisms of cancer cell invasion, Epithelial-to-Mesenchymal Transition, and metastatic spreading, by driving the expression of EMT-inducing transcription factors, cytokines, and microRNAs. Here we survey various strategies aimed at inhibiting tumor growth, metastatic dissemination, and drug resistance by interfering with Fra-1 expression, stability, and transcriptional activity. We summarize several tools aimed at the design and tumor-specific delivery of Fra-1/AP-1-specific drugs. Along with RNA-based therapeutics targeting the FOSL1 gene, its mRNA, or cognate regulatory circRNAs, we will examine the exploitation of blocking peptides, small molecule inhibitors, and innovative Fra-1 protein degraders. We also consider the possible caveats concerning Fra-1 inhibition in specific therapeutic contexts. Finally, we discuss a recent suicide gene therapy-based approach, aimed at selectively killing the Fra-1-overexpressing neoplastic cells. MDPI 2022-03-14 /pmc/articles/PMC8946526/ /pubmed/35326630 http://dx.doi.org/10.3390/cancers14061480 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Casalino, Laura Talotta, Francesco Cimmino, Amelia Verde, Pasquale The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting |
title | The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting |
title_full | The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting |
title_fullStr | The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting |
title_full_unstemmed | The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting |
title_short | The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting |
title_sort | fra-1/ap-1 oncoprotein: from the “undruggable” transcription factor to therapeutic targeting |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946526/ https://www.ncbi.nlm.nih.gov/pubmed/35326630 http://dx.doi.org/10.3390/cancers14061480 |
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