HMGA2 drives the IGFBP1/AKT pathway to counteract the increase in P27KIP1 protein levels in mtDNA/RNA‐less cancer cells

Recent comprehensive analyses of mtDNA and orthogonal RNA‐sequencing data revealed that in numerous human cancers, mtDNA copy numbers and mtRNA amounts are significantly reduced, followed by low respiratory gene expression. Under such conditions (called mt‐Low), cells encounter severe cell prolifera...

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Autores principales: Maruyama, Tsuyoshi, Saito, Koji, Higurashi, Masato, Ishikawa, Fumihiro, Kohno, Yohko, Mori, Kazunori, Shibanuma, Motoko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9807519/
https://www.ncbi.nlm.nih.gov/pubmed/36102493
http://dx.doi.org/10.1111/cas.15582
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author Maruyama, Tsuyoshi
Saito, Koji
Higurashi, Masato
Ishikawa, Fumihiro
Kohno, Yohko
Mori, Kazunori
Shibanuma, Motoko
author_facet Maruyama, Tsuyoshi
Saito, Koji
Higurashi, Masato
Ishikawa, Fumihiro
Kohno, Yohko
Mori, Kazunori
Shibanuma, Motoko
author_sort Maruyama, Tsuyoshi
collection PubMed
description Recent comprehensive analyses of mtDNA and orthogonal RNA‐sequencing data revealed that in numerous human cancers, mtDNA copy numbers and mtRNA amounts are significantly reduced, followed by low respiratory gene expression. Under such conditions (called mt‐Low), cells encounter severe cell proliferation defects; therefore, they must acquire countermeasures against this fatal disadvantage during malignant transformation. This study elucidated a countermeasure against the mt‐Low condition‐induced antiproliferative effects in hepatocellular carcinoma (HCC) cells. The mechanism relied on the architectural transcriptional regulator HMGA2, which was preferably expressed in HCC cells of the mt‐Low type in vitro and in vivo. Detailed in vitro analyses suggest that HMGA2 regulates insulin‐like growth factor binding protein 1 (IGFBP1) expression, leading to AKT activation, which then phosphorylates the cyclin‐dependent kinase inhibitor (CKI), P27KIP1, and facilitates its ubiquitin‐mediated degradation. Accordingly, intervention in the HMGA2 function by RNAi resulted in an increase in P27KIP1 levels and an induction of senescence‐like cell proliferation inhibition in mt‐Low‐type HCC cells. Conclusively, the HMGA2/IGFBP1/AKT axis has emerged as a countermeasure against P27KIP1 CKI upregulation under mt‐Low conditions, thereby circumventing cell proliferation inhibition and supporting the tumorigenic state. Notably, similar to in vitro cell lines, HMGA2 was likely to regulate IGFBP1 expression in HCC in vivo, thereby contributing to poor patient prognosis. Considering the significant number of cases under mt‐Low or the threat of CKI upregulation cancer‐wide, the axis is noteworthy as a vulnerability of cancer cells or target for tumor‐agnostic therapy inducing irreversible cell proliferation inhibition via CKI upregulation in a large population with cancer.
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spelling pubmed-98075192023-01-04 HMGA2 drives the IGFBP1/AKT pathway to counteract the increase in P27KIP1 protein levels in mtDNA/RNA‐less cancer cells Maruyama, Tsuyoshi Saito, Koji Higurashi, Masato Ishikawa, Fumihiro Kohno, Yohko Mori, Kazunori Shibanuma, Motoko Cancer Sci ORIGINAL ARTICLES Recent comprehensive analyses of mtDNA and orthogonal RNA‐sequencing data revealed that in numerous human cancers, mtDNA copy numbers and mtRNA amounts are significantly reduced, followed by low respiratory gene expression. Under such conditions (called mt‐Low), cells encounter severe cell proliferation defects; therefore, they must acquire countermeasures against this fatal disadvantage during malignant transformation. This study elucidated a countermeasure against the mt‐Low condition‐induced antiproliferative effects in hepatocellular carcinoma (HCC) cells. The mechanism relied on the architectural transcriptional regulator HMGA2, which was preferably expressed in HCC cells of the mt‐Low type in vitro and in vivo. Detailed in vitro analyses suggest that HMGA2 regulates insulin‐like growth factor binding protein 1 (IGFBP1) expression, leading to AKT activation, which then phosphorylates the cyclin‐dependent kinase inhibitor (CKI), P27KIP1, and facilitates its ubiquitin‐mediated degradation. Accordingly, intervention in the HMGA2 function by RNAi resulted in an increase in P27KIP1 levels and an induction of senescence‐like cell proliferation inhibition in mt‐Low‐type HCC cells. Conclusively, the HMGA2/IGFBP1/AKT axis has emerged as a countermeasure against P27KIP1 CKI upregulation under mt‐Low conditions, thereby circumventing cell proliferation inhibition and supporting the tumorigenic state. Notably, similar to in vitro cell lines, HMGA2 was likely to regulate IGFBP1 expression in HCC in vivo, thereby contributing to poor patient prognosis. Considering the significant number of cases under mt‐Low or the threat of CKI upregulation cancer‐wide, the axis is noteworthy as a vulnerability of cancer cells or target for tumor‐agnostic therapy inducing irreversible cell proliferation inhibition via CKI upregulation in a large population with cancer. John Wiley and Sons Inc. 2022-09-26 /pmc/articles/PMC9807519/ /pubmed/36102493 http://dx.doi.org/10.1111/cas.15582 Text en © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle ORIGINAL ARTICLES
Maruyama, Tsuyoshi
Saito, Koji
Higurashi, Masato
Ishikawa, Fumihiro
Kohno, Yohko
Mori, Kazunori
Shibanuma, Motoko
HMGA2 drives the IGFBP1/AKT pathway to counteract the increase in P27KIP1 protein levels in mtDNA/RNA‐less cancer cells
title HMGA2 drives the IGFBP1/AKT pathway to counteract the increase in P27KIP1 protein levels in mtDNA/RNA‐less cancer cells
title_full HMGA2 drives the IGFBP1/AKT pathway to counteract the increase in P27KIP1 protein levels in mtDNA/RNA‐less cancer cells
title_fullStr HMGA2 drives the IGFBP1/AKT pathway to counteract the increase in P27KIP1 protein levels in mtDNA/RNA‐less cancer cells
title_full_unstemmed HMGA2 drives the IGFBP1/AKT pathway to counteract the increase in P27KIP1 protein levels in mtDNA/RNA‐less cancer cells
title_short HMGA2 drives the IGFBP1/AKT pathway to counteract the increase in P27KIP1 protein levels in mtDNA/RNA‐less cancer cells
title_sort hmga2 drives the igfbp1/akt pathway to counteract the increase in p27kip1 protein levels in mtdna/rna‐less cancer cells
topic ORIGINAL ARTICLES
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9807519/
https://www.ncbi.nlm.nih.gov/pubmed/36102493
http://dx.doi.org/10.1111/cas.15582
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