Targeting the 3D genome by anthracyclines for chemotherapeutic effects

Abstract

The chromatin is folded into three-dimensional (3D) structures, and aberrant 3D chromatin folding has been implicated in cancer. We performed ATAC-seq and TOP2A ChIP-seq to assess the potential effects of various anthracycline drugs on the chromatin architecture. We found that specific anthracycline variants selectively disrupt chromatin looping anchors by interfering with CTCF binding, suggesting an additional therapeutic mechanism of anthracycline drugs targeting the 3D genome. Hi-C experiments in K562 cells treated with anthracycline drugs revealed widespread disruption of 3D chromatin organization, including altered long-range regulation at the Myc locus. Furthermore, AML patients treated with anthracycline drugs exhibited changes in chromatin structures near possible looping anchors, which were associated with distinct clinical outcomes. Together, our findings indicate that anthracycline drugs function as potent and selective epigenomic modulators, with the capacity to further target the 3D genome to exert anticancer effects, highlighting their potential for personalized therapy in tumors with aberrant 3D chromatin architecture. SignificanceChromatin structure plays a crucial role in regulating gene expression and maintaining cellular function. Aberrant chromatin 3D organization is a common feature in cancer. In this study, we investigate how anthracycline chemotherapy affects chromatin architecture using state-of-the-art genomic profiling techniques, including ATAC-seq, TOP2A ChIP-seq, CTCF ChIP-seq, and Hi-C. We show that certain anthracycline variants disrupt chromatin looping by interfering with CTCF binding, thereby altering the spatial genome organization. This disruption leads to changes in the regulation of associated genes, as exemplified by the Myc locus, and is associated with distinct clinical outcomes in AML patients. These findings highlight the potential of anthracycline drugs as therapeutics that target both the epigenome and 3D chromatin architecture, a promising strategy in personalized therapy.