KIF18b 依赖性 PARPBP 基因启动子低甲基化增强结直肠癌对奥沙利铂的耐药性。
KIF18b-dependent hypomethylation of PARPBP gene promoter enhances oxaliplatin resistance in colorectal cancer.
机构信息
Pharmaceutical Preparation Section, Sanmen People's Hospital of Zhejiang Province, Sanmen, 317100, China.
Department of Laboratory Medicine, Taizhou Enze Medical Center (Group) Enze Hospital, Taizhou, 318050, China.
出版信息
Exp Cell Res. 2021 Oct 15;407(2):112827. doi: 10.1016/j.yexcr.2021.112827. Epub 2021 Sep 9.
As the new platinum drug oxaliplatin has been widely used in clinical treatment of colorectal cancer (CRC), oxaliplatin resistance has become a burning problem. In this study, higher expression of PARP-1 binding protein (PARPBP) was detected in oxaliplatin-resistant CRC (OR-CRC) cells than in non-resistant cells. Further research showed that kinesin family member 18 b (KIF18b) induced the overexpression of PARPBP, sustaining oxaliplatin resistance in OR-CRC cells. Through exploring the PARPBP gene promoter, we found that SP1-recruited DNMT3b methylated PARPBP promoter to suppress transcription in CRC cells, and increased KIF18b attenuated the recruitment of DNMT3b to PARPBP promoter by directly interacting with SP1 in OR-CRC cells. Clinical analysis suggested a positive relationship between KIF18b and PARPBP in CRC tissues and indicated poor prognosis in CRC patients with high level of KIF18b or PARPBP. In summary, KIF18b-induced PARPBP contributes to the resistant phenotype of OR-CRC.
随着新的铂类药物奥沙利铂在结直肠癌（CRC）的临床治疗中得到广泛应用，奥沙利铂耐药已成为一个亟待解决的问题。在这项研究中，我们发现奥沙利铂耐药 CRC（OR-CRC）细胞中 PARP-1 结合蛋白（PARPBP）的表达高于非耐药细胞。进一步的研究表明，驱动蛋白家族成员 18b（KIF18b）诱导 PARPBP 的过表达，从而维持 OR-CRC 细胞对奥沙利铂的耐药性。通过探索 PARPBP 基因启动子，我们发现 SP1 募集的 DNMT3b 甲基化 PARPBP 启动子，从而抑制 CRC 细胞中的转录，并且在 OR-CRC 细胞中，KIF18b 通过直接与 SP1 相互作用，减弱了 DNMT3b 对 PARPBP 启动子的招募。临床分析表明，CRC 组织中 KIF18b 和 PARPBP 之间存在正相关关系，并提示 KIF18b 或 PARPBP 水平高的 CRC 患者预后不良。综上所述，KIF18b 诱导的 PARPBP 有助于 OR-CRC 的耐药表型。
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