m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5
Abstract Background Colon cancer (CC) cells can exhibit stemness and expansion capabilities, which contribute to resistance to conventional chemotherapies. Aberrant expression of CBX8 has been identified in many types of cancer, but the cause of this aberrant CBX8 expression and whether CBX8 is asso...
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doaj-734165857677487981609638c8f0b4a22020-12-20T12:20:28ZengBMCMolecular Cancer1476-45982019-12-0118111610.1186/s12943-019-1116-xm6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5Yi Zhang0Min Kang1Bin Zhang2Fanchao Meng3Jun Song4Hiroshi Kaneko5Fumio Shimamoto6Bo Tang7Department of Health Sciences, Hiroshima Shudo UniversityDepartment of Obstetrics, Gynecology and Reproductive Sciences, Yale School of MedicineDepartment of Oncology, The First Affiliated Hospital of Dalian Medical UniversityDepartment of General Surgery, Affiliated hospital of Xuzhou Medical UniversityDepartment of General Surgery, Affiliated hospital of Xuzhou Medical UniversityDepartment of Health Sciences, Hiroshima Shudo UniversityDepartment of Health Sciences, Hiroshima Shudo UniversityDepartment of Health Sciences, Hiroshima Shudo UniversityAbstract Background Colon cancer (CC) cells can exhibit stemness and expansion capabilities, which contribute to resistance to conventional chemotherapies. Aberrant expression of CBX8 has been identified in many types of cancer, but the cause of this aberrant CBX8 expression and whether CBX8 is associated with stemness properties in CC remain unknown. Methods qRT-PCR and IHC were applied to examine CBX8 levels in normal and chemoresistant CC tissues. Cancer cell stemness and chemosensitivity were evaluated by spheroid formation, colony formation, Western blot and flow cytometry assays. RNA-seq combined with ChIP-seq was used to identify target genes, and ChIP, IP and dual luciferase reporter assays were applied to explore the underlying mechanisms. Results CBX8 was significantly overexpressed in chemoresistant CC tissues. In addition, CBX8 could promote stemness and suppress chemosensitivity through LGR5. Mechanistic studies revealed that CBX8 activate the transcription of LGR5 in a noncanonical manner with assistance of Pol II. CBX8 recruited KMT2b to the LGR5 promoter, which maintained H3K4me3 status to promote LGR5 expression. Moreover, m6A methylation participated in the upregulation of CBX8 by maintaining CBX8 mRNA stability. Conclusions Upon m6A methylation-induced upregulation, CBX8 interacts with KMT2b and Pol II to promote LGR5 expression in a noncanonical manner, which contributes to increased cancer stemness and decreased chemosensitivity in CC. This study provides potential new therapeutic targets and valuable prognostic markers for CC.https://doi.org/10.1186/s12943-019-1116-xColon cancerCancer stemnessm6ACBX8 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yi Zhang Min Kang Bin Zhang Fanchao Meng Jun Song Hiroshi Kaneko Fumio Shimamoto Bo Tang |
spellingShingle |
Yi Zhang Min Kang Bin Zhang Fanchao Meng Jun Song Hiroshi Kaneko Fumio Shimamoto Bo Tang m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5 Molecular Cancer Colon cancer Cancer stemness m6A CBX8 |
author_facet |
Yi Zhang Min Kang Bin Zhang Fanchao Meng Jun Song Hiroshi Kaneko Fumio Shimamoto Bo Tang |
author_sort |
Yi Zhang |
title |
m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5 |
title_short |
m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5 |
title_full |
m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5 |
title_fullStr |
m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5 |
title_full_unstemmed |
m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5 |
title_sort |
m6a modification-mediated cbx8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of lgr5 |
publisher |
BMC |
series |
Molecular Cancer |
issn |
1476-4598 |
publishDate |
2019-12-01 |
description |
Abstract Background Colon cancer (CC) cells can exhibit stemness and expansion capabilities, which contribute to resistance to conventional chemotherapies. Aberrant expression of CBX8 has been identified in many types of cancer, but the cause of this aberrant CBX8 expression and whether CBX8 is associated with stemness properties in CC remain unknown. Methods qRT-PCR and IHC were applied to examine CBX8 levels in normal and chemoresistant CC tissues. Cancer cell stemness and chemosensitivity were evaluated by spheroid formation, colony formation, Western blot and flow cytometry assays. RNA-seq combined with ChIP-seq was used to identify target genes, and ChIP, IP and dual luciferase reporter assays were applied to explore the underlying mechanisms. Results CBX8 was significantly overexpressed in chemoresistant CC tissues. In addition, CBX8 could promote stemness and suppress chemosensitivity through LGR5. Mechanistic studies revealed that CBX8 activate the transcription of LGR5 in a noncanonical manner with assistance of Pol II. CBX8 recruited KMT2b to the LGR5 promoter, which maintained H3K4me3 status to promote LGR5 expression. Moreover, m6A methylation participated in the upregulation of CBX8 by maintaining CBX8 mRNA stability. Conclusions Upon m6A methylation-induced upregulation, CBX8 interacts with KMT2b and Pol II to promote LGR5 expression in a noncanonical manner, which contributes to increased cancer stemness and decreased chemosensitivity in CC. This study provides potential new therapeutic targets and valuable prognostic markers for CC. |
topic |
Colon cancer Cancer stemness m6A CBX8 |
url |
https://doi.org/10.1186/s12943-019-1116-x |
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