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Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2024 | Research

The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability

Authors: Etna Abad, Jérémy Sandoz, Gerard Romero, Ivan Zadra, Julia Urgel-Solas, Pablo Borredat, Savvas Kourtis, Laura Ortet, Carlos M. Martínez, Donate Weghorn, Sara Sdelci, Ana Janic

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

Abstract

Background

TP53, the most frequently mutated gene in human cancers, orchestrates a complex transcriptional program crucial for cancer prevention. While certain TP53-dependent genes have been extensively studied, others, like the recently identified RNF144B, remained poorly understood. This E3 ubiquitin ligase has shown potent tumor suppressor activity in murine Eμ Myc-driven lymphoma, emphasizing its significance in the TP53 network. However, little is known about its targets and its role in cancer development, requiring further exploration. In this work, we investigate RNF144B's impact on tumor suppression beyond the hematopoietic compartment in human cancers.

Methods

Employing TP53 wild-type cells, we generated models lacking RNF144B in both non-transformed and cancerous cells of human and mouse origin. By using proteomics, transcriptomics, and functional analysis, we assessed RNF144B's impact in cellular proliferation and transformation. Through in vitro and in vivo experiments, we explored proliferation, DNA repair, cell cycle control, mitotic progression, and treatment resistance. Findings were contrasted with clinical datasets and bioinformatics analysis.

Results

Our research underscores RNF144B's pivotal role as a tumor suppressor, particularly in lung adenocarcinoma. In both human and mouse oncogene-expressing cells, RNF144B deficiency heightened cellular proliferation and transformation. Proteomic and transcriptomic analysis revealed RNF144B's novel function in mediating protein degradation associated with cell cycle progression, DNA damage response and genomic stability. RNF144B deficiency induced chromosomal instability, mitotic defects, and correlated with elevated aneuploidy and worse prognosis in human tumors. Furthermore, RNF144B-deficient lung adenocarcinoma cells exhibited resistance to cell cycle inhibitors that induce chromosomal instability.

Conclusions

Supported by clinical data, our study suggests that RNF144B plays a pivotal role in maintaining genomic stability during tumor suppression.

Graphical Abstract

Available only for authorised users

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Title: The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability
Authors: Etna Abad
Jérémy Sandoz
Gerard Romero
Ivan Zadra
Julia Urgel-Solas
Pablo Borredat
Savvas Kourtis
Laura Ortet
Carlos M. Martínez
Donate Weghorn
Sara Sdelci
Ana Janic
Publication date: 01-12-2024
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-024-03045-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

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Keynote webinar | Spotlight on antibody–drug conjugates in cancer