Cargando…

Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer

Forkhead box transcription factor M1 (FOXM1) is a proliferation‐associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells (DCs). Although previous work has shown that FOXM1 enhances DC maturation in re...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhou, Zhongshi, Chen, Hongdan, Xie, Rui, Wang, Hongjie, Li, Senlin, Xu, Qianqian, Xu, Na, Cheng, Qi, Qian, Ying, Huang, Rongrong, Shao, Zekun, Xiang, Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441919/
https://www.ncbi.nlm.nih.gov/pubmed/30628173
http://dx.doi.org/10.1002/1878-0261.12443
_version_ 1783407625203875840
author Zhou, Zhongshi
Chen, Hongdan
Xie, Rui
Wang, Hongjie
Li, Senlin
Xu, Qianqian
Xu, Na
Cheng, Qi
Qian, Ying
Huang, Rongrong
Shao, Zekun
Xiang, Ming
author_facet Zhou, Zhongshi
Chen, Hongdan
Xie, Rui
Wang, Hongjie
Li, Senlin
Xu, Qianqian
Xu, Na
Cheng, Qi
Qian, Ying
Huang, Rongrong
Shao, Zekun
Xiang, Ming
author_sort Zhou, Zhongshi
collection PubMed
description Forkhead box transcription factor M1 (FOXM1) is a proliferation‐associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells (DCs). Although previous work has shown that FOXM1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM1 affects DC maturation in the context of tumor‐specific immunity. In this study, we examined the central role of FOXM1 in regulating bone marrow‐derived dendritic cell (BMDC) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM1 retarded maturation phenotypes of BMDCs, inhibited promotion of T‐cell proliferation, and decreased interleukin‐12 (IL‐12) p70 in tumor‐bearing mice (TBM). Notably, FOXM1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDCs. Increased H3K79me2 enrichment was observed at the FOXM1 promoter in both BMDCs from TBM, and in BMDCs from wild‐type mice cultured with tumor‐conditioned medium that mimics the tumor microenvironment (TME). Furthermore, inhibition of the H3K79 methyltransferase DOT1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM1 and partially reversed its immunosuppressive effects on BMDCs. Furthermore, we found that FOXM1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDCs in vitro; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDCs through the Wnt5a signaling pathway, and thus provide novel insights into FOXM1‐based antitumor immunotherapy.
format Online
Article
Text
id pubmed-6441919
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-64419192019-04-11 Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer Zhou, Zhongshi Chen, Hongdan Xie, Rui Wang, Hongjie Li, Senlin Xu, Qianqian Xu, Na Cheng, Qi Qian, Ying Huang, Rongrong Shao, Zekun Xiang, Ming Mol Oncol Research Articles Forkhead box transcription factor M1 (FOXM1) is a proliferation‐associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells (DCs). Although previous work has shown that FOXM1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM1 affects DC maturation in the context of tumor‐specific immunity. In this study, we examined the central role of FOXM1 in regulating bone marrow‐derived dendritic cell (BMDC) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM1 retarded maturation phenotypes of BMDCs, inhibited promotion of T‐cell proliferation, and decreased interleukin‐12 (IL‐12) p70 in tumor‐bearing mice (TBM). Notably, FOXM1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDCs. Increased H3K79me2 enrichment was observed at the FOXM1 promoter in both BMDCs from TBM, and in BMDCs from wild‐type mice cultured with tumor‐conditioned medium that mimics the tumor microenvironment (TME). Furthermore, inhibition of the H3K79 methyltransferase DOT1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM1 and partially reversed its immunosuppressive effects on BMDCs. Furthermore, we found that FOXM1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDCs in vitro; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDCs through the Wnt5a signaling pathway, and thus provide novel insights into FOXM1‐based antitumor immunotherapy. John Wiley and Sons Inc. 2019-02-15 2019-04 /pmc/articles/PMC6441919/ /pubmed/30628173 http://dx.doi.org/10.1002/1878-0261.12443 Text en © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Zhou, Zhongshi
Chen, Hongdan
Xie, Rui
Wang, Hongjie
Li, Senlin
Xu, Qianqian
Xu, Na
Cheng, Qi
Qian, Ying
Huang, Rongrong
Shao, Zekun
Xiang, Ming
Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer
title Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer
title_full Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer
title_fullStr Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer
title_full_unstemmed Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer
title_short Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer
title_sort epigenetically modulated foxm1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441919/
https://www.ncbi.nlm.nih.gov/pubmed/30628173
http://dx.doi.org/10.1002/1878-0261.12443
work_keys_str_mv AT zhouzhongshi epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT chenhongdan epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT xierui epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT wanghongjie epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT lisenlin epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT xuqianqian epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT xuna epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT chengqi epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT qianying epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT huangrongrong epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT shaozekun epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer
AT xiangming epigeneticallymodulatedfoxm1suppressesdendriticcellmaturationinpancreaticcancerandcoloncancer