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SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation
SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is a histone H3K9 methyltransferase that stimulates cell proliferation by methylating AKT, which contributes to drug resistance in multiple myeloma (MM). Lenalidomide is an immunomodulatory agent widely used in the treatment of MM. Ho...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10189757/ https://www.ncbi.nlm.nih.gov/pubmed/37206551 http://dx.doi.org/10.3892/etm.2023.11973 |
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author | Qian, Xiaoli Yang, Yang Deng, Yingfen Liu, Yali Zhou, Yuwen Han, Fang Xu, Yue Yuan, Hongjian |
author_facet | Qian, Xiaoli Yang, Yang Deng, Yingfen Liu, Yali Zhou, Yuwen Han, Fang Xu, Yue Yuan, Hongjian |
author_sort | Qian, Xiaoli |
collection | PubMed |
description | SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is a histone H3K9 methyltransferase that stimulates cell proliferation by methylating AKT, which contributes to drug resistance in multiple myeloma (MM). Lenalidomide is an immunomodulatory agent widely used in the treatment of MM. However, lenalidomide resistance occurs in patients with MM. Currently, the role of SETDB1 in lenalidomide resistance in MM remains unclear. Thus, the present study aimed to explore the functional association between SETDB1 and lenalidomide resistance in MM. The analysis of GEO datasets revealed that SETDB1 was upregulated in lenalidomide-resistant MM cells and that its expression was associated with poor prognosis of patients with MM. Apoptosis analysis revealed that overexpression of SETDB1 in MM cells significantly decreased apoptosis, while knockdown of SETDB1 increased apoptosis. Furthermore, the IC(50) value of lenalidomide in MM cells increased following SETDB1 overexpression and decreased following SETDB1 silencing. Additionally, SETDB1 mediated epithelial-mesenchymal transition (EMT) and activated the PI3K/AKT pathway. Mechanistic analysis revealed that inhibition of PI3K/AKT signaling in MM cells increased apoptosis, sensitized the cells to lenalidomide and inhibited EMT, whereas SETDB1 overexpression inhibited the effects of PI3K/AKT cascade inhibition. In conclusion, the findings of the present study indicated that SETDB1 promoted lenalidomide resistance in MM cells by promoting EMT and the PI3K/AKT signaling pathway. Thus, SETDB1 may be a potential therapeutic target for MM. |
format | Online Article Text |
id | pubmed-10189757 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-101897572023-05-18 SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation Qian, Xiaoli Yang, Yang Deng, Yingfen Liu, Yali Zhou, Yuwen Han, Fang Xu, Yue Yuan, Hongjian Exp Ther Med Articles SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is a histone H3K9 methyltransferase that stimulates cell proliferation by methylating AKT, which contributes to drug resistance in multiple myeloma (MM). Lenalidomide is an immunomodulatory agent widely used in the treatment of MM. However, lenalidomide resistance occurs in patients with MM. Currently, the role of SETDB1 in lenalidomide resistance in MM remains unclear. Thus, the present study aimed to explore the functional association between SETDB1 and lenalidomide resistance in MM. The analysis of GEO datasets revealed that SETDB1 was upregulated in lenalidomide-resistant MM cells and that its expression was associated with poor prognosis of patients with MM. Apoptosis analysis revealed that overexpression of SETDB1 in MM cells significantly decreased apoptosis, while knockdown of SETDB1 increased apoptosis. Furthermore, the IC(50) value of lenalidomide in MM cells increased following SETDB1 overexpression and decreased following SETDB1 silencing. Additionally, SETDB1 mediated epithelial-mesenchymal transition (EMT) and activated the PI3K/AKT pathway. Mechanistic analysis revealed that inhibition of PI3K/AKT signaling in MM cells increased apoptosis, sensitized the cells to lenalidomide and inhibited EMT, whereas SETDB1 overexpression inhibited the effects of PI3K/AKT cascade inhibition. In conclusion, the findings of the present study indicated that SETDB1 promoted lenalidomide resistance in MM cells by promoting EMT and the PI3K/AKT signaling pathway. Thus, SETDB1 may be a potential therapeutic target for MM. D.A. Spandidos 2023-04-21 /pmc/articles/PMC10189757/ /pubmed/37206551 http://dx.doi.org/10.3892/etm.2023.11973 Text en Copyright: © Qian et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Qian, Xiaoli Yang, Yang Deng, Yingfen Liu, Yali Zhou, Yuwen Han, Fang Xu, Yue Yuan, Hongjian SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation |
title | SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation |
title_full | SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation |
title_fullStr | SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation |
title_full_unstemmed | SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation |
title_short | SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation |
title_sort | setdb1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and pi3k/akt pathway activation |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10189757/ https://www.ncbi.nlm.nih.gov/pubmed/37206551 http://dx.doi.org/10.3892/etm.2023.11973 |
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