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Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation

The epigenetic silencing of tumor suppressor genes in myelodysplastic syndromes (MDS) can potentially confer a growth advantage to individual cellular clones. Currently, the recommended treatment for patients with high-risk MDS is the methylation agent decitabine (DAC), a drug that can induce the re...

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Autores principales: Zeng, Wen, Dai, Hanjun, Yan, Ming, Cai, Xiaojun, Luo, Hong, Ke, Min, Liu, Zeming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662805/
https://www.ncbi.nlm.nih.gov/pubmed/29124072
http://dx.doi.org/10.1155/2017/4302320
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author Zeng, Wen
Dai, Hanjun
Yan, Ming
Cai, Xiaojun
Luo, Hong
Ke, Min
Liu, Zeming
author_facet Zeng, Wen
Dai, Hanjun
Yan, Ming
Cai, Xiaojun
Luo, Hong
Ke, Min
Liu, Zeming
author_sort Zeng, Wen
collection PubMed
description The epigenetic silencing of tumor suppressor genes in myelodysplastic syndromes (MDS) can potentially confer a growth advantage to individual cellular clones. Currently, the recommended treatment for patients with high-risk MDS is the methylation agent decitabine (DAC), a drug that can induce the reexpression of silenced tumor suppressor genes. We investigated the effects of DAC treatment on the myeloid MDS cell line SKM-1 and investigated the role of FOXO3A, a potentially tumor-suppressive transcription factor, by silencing its expression prior to DAC treatment. We found that FOXO3A exists in an inactive, hyperphosphorylated form in SKM-1 cells, but that DAC both induces FOXO3A expression and reactivates the protein by reducing its phosphorylation level. Furthermore, we show that this FOXO3A activation is responsible for the DAC-induced differentiation of SKM-1 cells into monocytes, as well as for SKM-1 cell cycle arrest, apoptosis, and autophagy. Collectively, these results suggest that FOXO3A reactivation may contribute to the therapeutic effects of DAC in MDS.
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spelling pubmed-56628052017-11-09 Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation Zeng, Wen Dai, Hanjun Yan, Ming Cai, Xiaojun Luo, Hong Ke, Min Liu, Zeming J Immunol Res Research Article The epigenetic silencing of tumor suppressor genes in myelodysplastic syndromes (MDS) can potentially confer a growth advantage to individual cellular clones. Currently, the recommended treatment for patients with high-risk MDS is the methylation agent decitabine (DAC), a drug that can induce the reexpression of silenced tumor suppressor genes. We investigated the effects of DAC treatment on the myeloid MDS cell line SKM-1 and investigated the role of FOXO3A, a potentially tumor-suppressive transcription factor, by silencing its expression prior to DAC treatment. We found that FOXO3A exists in an inactive, hyperphosphorylated form in SKM-1 cells, but that DAC both induces FOXO3A expression and reactivates the protein by reducing its phosphorylation level. Furthermore, we show that this FOXO3A activation is responsible for the DAC-induced differentiation of SKM-1 cells into monocytes, as well as for SKM-1 cell cycle arrest, apoptosis, and autophagy. Collectively, these results suggest that FOXO3A reactivation may contribute to the therapeutic effects of DAC in MDS. Hindawi 2017 2017-10-16 /pmc/articles/PMC5662805/ /pubmed/29124072 http://dx.doi.org/10.1155/2017/4302320 Text en Copyright © 2017 Wen Zeng et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Zeng, Wen
Dai, Hanjun
Yan, Ming
Cai, Xiaojun
Luo, Hong
Ke, Min
Liu, Zeming
Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation
title Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation
title_full Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation
title_fullStr Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation
title_full_unstemmed Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation
title_short Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation
title_sort decitabine-induced changes in human myelodysplastic syndrome cell line skm-1 are mediated by foxo3a activation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662805/
https://www.ncbi.nlm.nih.gov/pubmed/29124072
http://dx.doi.org/10.1155/2017/4302320
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