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Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity
INTRODUCTION: Breast tumor development is regulated by a sub-population of breast cancer cells, termed cancer stem-like cells (CSC), which are capable of self-renewing and differentiating, and are involved in promoting breast cancer invasion, metastasis, drug resistance and relapse. CSCs are highly...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10155275/ https://www.ncbi.nlm.nih.gov/pubmed/37152043 http://dx.doi.org/10.3389/fonc.2023.1141834 |
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author | Le Minh, Giang Esquea, Emily M. Dhameliya, Tejsi T. Merzy, Jessica Lee, Mi-Hye Ball, Lauren E. Reginato, Mauricio J. |
author_facet | Le Minh, Giang Esquea, Emily M. Dhameliya, Tejsi T. Merzy, Jessica Lee, Mi-Hye Ball, Lauren E. Reginato, Mauricio J. |
author_sort | Le Minh, Giang |
collection | PubMed |
description | INTRODUCTION: Breast tumor development is regulated by a sub-population of breast cancer cells, termed cancer stem-like cells (CSC), which are capable of self-renewing and differentiating, and are involved in promoting breast cancer invasion, metastasis, drug resistance and relapse. CSCs are highly adaptable, capable of reprogramming their own metabolism and signaling activity in response to stimuli within the tumor microenvironment. Recently, the nutrient sensor O-GlcNAc transferase (OGT) and O-GlcNAcylation was shown to be enriched in CSC populations, where it promotes the stemness and tumorigenesis of breast cancer cells in vitro and in vivo. This enrichment was associated with upregulation of the transcription factor Kruppel-like-factor 8 (KLF8) suggesting a potential role of KLF8 in regulating CSCs properties. METHODS: Triple-negative breast cancer cells were genetically modified to generate KLF8 overexpressing or KLF8 knock-down cells. Cancer cells, control or with altered KLF8 expression were analyzed to assess mammosphere formation efficiency, CSCs frequency and expression of CSCs factors. Tumor growth in vivo of control or KLF8 knock-down cells was assessed by fat-pad injection of these cell in immunocompromised mice. RESULTS: Here, we show that KLF8 is required and sufficient for regulating CSC phenotypes and regulating transcription factors SOX2, NANOG, OCT4 and c-MYC. KLF8 levels are associated with chemoresistance in triple negative breast cancer patients and overexpression in breast cancer cells increased paclitaxel resistance. KLF8 and OGT co-regulate each other to form a feed-forward loop to promote CSCs phenotype and mammosphere formation of breast cancer cells. DISCUSSION: These results suggest a critical role of KLF8 and OGT in promoting CSCs and cancer progression, that may serve as potential targets for developing strategy to target CSCs specifically. |
format | Online Article Text |
id | pubmed-10155275 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101552752023-05-04 Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity Le Minh, Giang Esquea, Emily M. Dhameliya, Tejsi T. Merzy, Jessica Lee, Mi-Hye Ball, Lauren E. Reginato, Mauricio J. Front Oncol Oncology INTRODUCTION: Breast tumor development is regulated by a sub-population of breast cancer cells, termed cancer stem-like cells (CSC), which are capable of self-renewing and differentiating, and are involved in promoting breast cancer invasion, metastasis, drug resistance and relapse. CSCs are highly adaptable, capable of reprogramming their own metabolism and signaling activity in response to stimuli within the tumor microenvironment. Recently, the nutrient sensor O-GlcNAc transferase (OGT) and O-GlcNAcylation was shown to be enriched in CSC populations, where it promotes the stemness and tumorigenesis of breast cancer cells in vitro and in vivo. This enrichment was associated with upregulation of the transcription factor Kruppel-like-factor 8 (KLF8) suggesting a potential role of KLF8 in regulating CSCs properties. METHODS: Triple-negative breast cancer cells were genetically modified to generate KLF8 overexpressing or KLF8 knock-down cells. Cancer cells, control or with altered KLF8 expression were analyzed to assess mammosphere formation efficiency, CSCs frequency and expression of CSCs factors. Tumor growth in vivo of control or KLF8 knock-down cells was assessed by fat-pad injection of these cell in immunocompromised mice. RESULTS: Here, we show that KLF8 is required and sufficient for regulating CSC phenotypes and regulating transcription factors SOX2, NANOG, OCT4 and c-MYC. KLF8 levels are associated with chemoresistance in triple negative breast cancer patients and overexpression in breast cancer cells increased paclitaxel resistance. KLF8 and OGT co-regulate each other to form a feed-forward loop to promote CSCs phenotype and mammosphere formation of breast cancer cells. DISCUSSION: These results suggest a critical role of KLF8 and OGT in promoting CSCs and cancer progression, that may serve as potential targets for developing strategy to target CSCs specifically. Frontiers Media S.A. 2023-04-19 /pmc/articles/PMC10155275/ /pubmed/37152043 http://dx.doi.org/10.3389/fonc.2023.1141834 Text en Copyright © 2023 Le Minh, Esquea, Dhameliya, Merzy, Lee, Ball and Reginato https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Le Minh, Giang Esquea, Emily M. Dhameliya, Tejsi T. Merzy, Jessica Lee, Mi-Hye Ball, Lauren E. Reginato, Mauricio J. Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity |
title | Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity |
title_full | Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity |
title_fullStr | Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity |
title_full_unstemmed | Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity |
title_short | Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity |
title_sort | kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10155275/ https://www.ncbi.nlm.nih.gov/pubmed/37152043 http://dx.doi.org/10.3389/fonc.2023.1141834 |
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