Abstract
BackgroundColon 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.MethodsqRT-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.ResultsCBX8 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.ConclusionsUpon 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.
Highlights
Colon cancer (CC) cells can exhibit stemness and expansion capabilities, which contribute to resistance to conventional chemotherapies
CBX8 maintains the stemness properties of CC cells We used The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database to analyze the mRNA expression profiles of CBX proteins in normal colon tissues (n = 349) and CC tissues (n = 275), finding that the expression of CBX2, CBX4 and CBX8 was significantly upregulated in CC tissues (Additional file 1: Figure S1A)
As chemoresistance is a key feature of cancer stemness, we investigated the effect of CBX8 on the stemness features of CC cells
Summary
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. Colon cancer (CC) is a leading cause of cancer-related death in many countries [1]. Accumulating evidence has demonstrated that a distinct tumor cell subpopulation with stemness, known as the cancer stem cell (CSC) population, exists in CC [2]. CSCs can self-renew and expand, contributing to progression of tumors and resistance to conventional therapies [3]. Whether CBX8 is associated with stemness properties and chemosensitivity remains unknown and needs further exploration in the context of CC
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