Alteration of chromatin high-order conformation associated with oxaliplatin resistance acquisition in colorectal cancer cells.
Alteration of chromatin high-order conformation associated with oxaliplatin resistance acquisition in colorectal cancer cells.
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DOI：
10.1002/exp.20220136
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发表时间：
2023-08
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影响因子：
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通讯作者：
Du, Lutao
中科院分区：
文献类型：
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作者：
Li, Peilong;Shang, Xueying;Jiao, Qinlian;Mi, Qi;Zhu, Mengqian;Ren, Yidan;Li, Juan;Li, Li;Liu, Jin;Wang, Chuanxin;Shi, Yi;Wang, Yunshan;Du, Lutao
奥沙利铂是广泛用于结直肠癌（CRC）治疗的一线化疗药物。然而，很大一部分患者倾向于对奥沙利铂产生耐药性，导致化疗失败。目前，关于奥沙利铂耐药的研究主要集中在癌症演变过程中的遗传学和表观遗传学改变，而基因组的高阶三维（3D）构象特征尚待探索。为了研究奥沙利铂耐药过程中染色质构象的变化，我们结合DLO Hi-C、ChIP-seq和RNA-seq技术对已建立的奥沙利铂耐药细胞系HCT 116-OxR以及对照细胞系HCT 116进行了多组学研究。结果表明，耐药后有19.33%的基因组区域发生A/B区室转化，进一步分析A/B区室转化的基因表明，肿瘤细胞奥沙利铂耐药的获得与活性氧减少和转移能力增强有关。我们的研究基于DLO Hi-C和其他表观遗传组学实验揭示了CRC细胞和奥沙利铂耐药细胞之间的空间染色质结构差异。更重要的是，我们为奥沙利铂耐药的癌症治疗提供了潜在的靶点，并为从3D基因组改变的角度研究耐药行为提供了新的途径。我们的研究基于DLO Hi-C和其他表观遗传组学实验揭示了结直肠癌（CRC）细胞和奥沙利铂耐药细胞之间的空间染色质结构差异。更重要的是，我们提供了一系列A/B区室转换基因作为奥沙利铂耐药肿瘤治疗的潜在靶点，并找到了一种在3D基因组改变视角下研究耐药行为的新途径。
Oxaliplatin is a first‐line chemotherapy drug widely adopted in colorectal cancer (CRC) treatment. However, a large proportion of patients tend to become resistant to oxaliplatin, causing chemotherapy to fail. At present, researches on oxaliplatin resistance mainly focus on the genetic and epigenetic alterations during cancer evolution, while the characteristics of high‐order three‐dimensional (3D) conformation of genome are yet to be explored. In order to investigate the chromatin conformation alteration during oxaliplatin resistance, we performed multi‐omics study by combining DLO Hi‐C, ChIP‐seq as well as RNA‐seq technologies on the established oxaliplatin‐resistant cell line HCT116‐OxR, as well as the control cell line HCT116. The results indicate that 19.33% of the genome regions have A/B compartments transformation after drug resistance, further analysis of the genes converted by A/B compartments reveals that the acquisition of oxaliplatin resistance in tumor cells is related to the reduction of reactive oxygen species and enhanced metastatic capacity. Our research reveals the spatial chromatin structural difference between CRC cells and oxaliplatin resistant cells based on the DLO Hi‐C and other epigenetic omics experiments. More importantly, we provide potential targets for oxaliplatin‐resistant cancer treatment and a new way to investigate drug resistance behavior under the perspective of 3D genome alteration. Our research reveals the spatial chromatin structural difference between colorectal cancer (CRC) cells and oxaliplatin resistant cells based on the DLO Hi‐C and other epigenetic omics experiments. More importantly, we provide a series of A/B compartment switching genes as potential targets for oxaliplatin‐resistant cancer treatment and find a new way to investigate drug resistance behavior under the perspective of 3D genome alteration.