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A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity

Epithelial–mesenchymal transition (EMT) is an important axis of phenotypic plasticity—a hallmark of cancer metastasis. Raf kinase-B inhibitor protein (RKIP) and BTB and CNC homology 1 (BACH1) are reported to influence EMT. In breast cancer, they act antagonistically, but the exact nature of their ro...

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Autores principales: Shyam, Sai, Ramu, Soundharya, Sehgal, Manas, Jolly, Mohit Kumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10645512/
https://www.ncbi.nlm.nih.gov/pubmed/37963558
http://dx.doi.org/10.1098/rsif.2023.0389
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author Shyam, Sai
Ramu, Soundharya
Sehgal, Manas
Jolly, Mohit Kumar
author_facet Shyam, Sai
Ramu, Soundharya
Sehgal, Manas
Jolly, Mohit Kumar
author_sort Shyam, Sai
collection PubMed
description Epithelial–mesenchymal transition (EMT) is an important axis of phenotypic plasticity—a hallmark of cancer metastasis. Raf kinase-B inhibitor protein (RKIP) and BTB and CNC homology 1 (BACH1) are reported to influence EMT. In breast cancer, they act antagonistically, but the exact nature of their roles in mediating EMT and associated other axes of plasticity remains unclear. Here, analysing transcriptomic data, we reveal their antagonistic trends in a pan-cancer manner in terms of association with EMT, metabolic reprogramming and immune evasion via PD-L1. Next, we developed and simulated a mechanism-based gene regulatory network that captures how RKIP and BACH1 engage in feedback loops with drivers of EMT and stemness. We found that RKIP and BACH1 belong to two antagonistic ‘teams’ of players—while BACH1 belonged to the one driving pro-EMT, stem-like and therapy-resistant cell states, RKIP belonged to the one enabling pro-epithelial, less stem-like and therapy-sensitive phenotypes. Finally, we observed that low RKIP levels and upregulated BACH1 levels associated with worse clinical outcomes in many cancer types. Together, our systems-level analysis indicates that the emergent dynamics of underlying regulatory network enable the antagonistic patterns of RKIP and BACH1 with various axes of cancer cell plasticity, and with patient survival data.
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spelling pubmed-106455122023-11-15 A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity Shyam, Sai Ramu, Soundharya Sehgal, Manas Jolly, Mohit Kumar J R Soc Interface Life Sciences–Mathematics interface Epithelial–mesenchymal transition (EMT) is an important axis of phenotypic plasticity—a hallmark of cancer metastasis. Raf kinase-B inhibitor protein (RKIP) and BTB and CNC homology 1 (BACH1) are reported to influence EMT. In breast cancer, they act antagonistically, but the exact nature of their roles in mediating EMT and associated other axes of plasticity remains unclear. Here, analysing transcriptomic data, we reveal their antagonistic trends in a pan-cancer manner in terms of association with EMT, metabolic reprogramming and immune evasion via PD-L1. Next, we developed and simulated a mechanism-based gene regulatory network that captures how RKIP and BACH1 engage in feedback loops with drivers of EMT and stemness. We found that RKIP and BACH1 belong to two antagonistic ‘teams’ of players—while BACH1 belonged to the one driving pro-EMT, stem-like and therapy-resistant cell states, RKIP belonged to the one enabling pro-epithelial, less stem-like and therapy-sensitive phenotypes. Finally, we observed that low RKIP levels and upregulated BACH1 levels associated with worse clinical outcomes in many cancer types. Together, our systems-level analysis indicates that the emergent dynamics of underlying regulatory network enable the antagonistic patterns of RKIP and BACH1 with various axes of cancer cell plasticity, and with patient survival data. The Royal Society 2023-11-15 /pmc/articles/PMC10645512/ /pubmed/37963558 http://dx.doi.org/10.1098/rsif.2023.0389 Text en © 2023 The Authors. https://creativecommons.org/licenses/by/4.0/Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, provided the original author and source are credited.
spellingShingle Life Sciences–Mathematics interface
Shyam, Sai
Ramu, Soundharya
Sehgal, Manas
Jolly, Mohit Kumar
A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity
title A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity
title_full A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity
title_fullStr A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity
title_full_unstemmed A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity
title_short A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity
title_sort systems-level analysis of the mutually antagonistic roles of rkip and bach1 in dynamics of cancer cell plasticity
topic Life Sciences–Mathematics interface
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10645512/
https://www.ncbi.nlm.nih.gov/pubmed/37963558
http://dx.doi.org/10.1098/rsif.2023.0389
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