Author:
Zhang Yi,Kang Min,Zhang Bin,Meng Fanchao,Song Jun,Kaneko Hiroshi,Shimamoto Fumio,Tang Bo
Abstract
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.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Jiangsu Province
China Postdoctoral Science Foundation
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine
Cited by
99 articles.
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