Abstract

Molecular crosstalk between the cellular epigenome and genome converge as a synergistic driver of oncogenic transformations. Besides other pathways, epigenetic regulatory circuits exert their effect towards cancer progression through the induction of DNA repair deficiencies. We explored this mechanism using a camptothecin encapsulated in β-cyclodextrin–EDTA–Fe3O4 nanoparticles (CPT-CEF)-treated HT29 cells model. We previously demonstrated that CPT-CEF treatment of HT29 cells effectively induces apoptosis and cell cycle arrest, stalling cancer progression. A comparative transcriptome analysis of CPT-CEF-treated versus untreated HT29 cells indicated that genes controlling mismatch repair, base excision repair, and homologues recombination were downregulated in these cancer cells. Our study demonstrated that treatment with CPT-CEF alleviated this repression. We observed that CPT-CEF exerts its effect by possibly affecting the DNA repair mechanism through epigenetic modulation involving genes of HMGB1, APEX1, and POLE3. Hence, we propose that CPT-CEF could be a DNA repair modulator that harnesses the cell’s epigenomic plasticity to amend DNA repair deficiencies in cancer cells.

Highlights

  • Epigenetic mechanisms are essential for the ontogenesis of mammals and the maintenance of tissue-specific gene expression [1,2]

  • Our results reveal three important genes, High mobility group box 1 (HMGB1), APEX1, and POLE3, that function in the epigenetic control of a DNA-repair mechanism, which modulates cancer in HT29 cells, and induce apoptosis

  • In the context of epigenetic study of cancer cell development, the analysis indicated that treatment with camptothecin encapsulated in β-cyclodextrin–EDTA–Fe3O4 nanoparticles (CPT-CEF) could reverse these deficiencies by modulating the expression of these genes

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Summary

Introduction

Epigenetic mechanisms are essential for the ontogenesis of mammals and the maintenance of tissue-specific gene expression [1,2]. The two common types present in tumors are demethylation and de novo methylation of CpG islands [10]. These result in expression profiles that promote tumor growth. The deregulation of this process affects the maintenance of repressive chromatin, thereby causing an aberrant promotion of gene expression [11]. This characteristic makes epigenetic modifications a perfect target for therapeutic intervention for cancer [12]

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