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KIF18b-dependent hypomethylation of PARPBP gene promoter enhances oxaliplatin resistance in colorectal cancer
Experimental Cell Research ( IF 3.3 ) Pub Date : 2021-09-09 , DOI: 10.1016/j.yexcr.2021.112827
Bing Hong 1 , Ruyue Lu 2 , Wanshuang Lou 3 , Yuyan Bao 1 , Lei Qiao 4 , Yanyan Hu 5 , Kaiping Liu 1 , Jiaoe Chen 6 , Danni Bao 5 , Ming Ye 7 , Zejun Fang 5 , Chaoju Gong 4 , Xiaomin Zhang 1
Affiliation  

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.



中文翻译:

PARPBP基因启动子的KIF18b依赖性低甲基化增强了结直肠癌的奥沙利铂耐药性

随着铂类新药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,在奥沙利铂耐药的 CRC (OR-CRC) 细胞中检测到 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 18 b (KIF18b) 诱导 PARPBP 的过度表达,维持 OR-CRC 细胞中的奥沙利​​铂耐药性。通过探索PARPBP基因启动子,我们发现SP1募集的DNMT3b甲基化PARPBP启动子抑制CRC细胞中的转录,增加KIF18b通过直接与OR-CRC细胞中的SP1相互作用减弱DNMT3b向PARPBP启动子的募集。临床分析表明 CRC 组织中 KIF18b 和 PARPBP 之间存在正相关关系,表明 KIF18b 或 PARPBP 水平高的 CRC 患者预后不良。总之,KIF18b 诱导的 PARPBP 有助于 OR-CRC 的耐药表型。

更新日期:2021-09-15
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