A p53-stabilizing agent, CP-31398, induces p21 expression with increased G2/M phase through the YY1 transcription factor in esophageal carcinoma defective of the p53 pathway.
A p53-stabilizing agent, CP-31398, induces p21 expression with increased G2/M phase through the YY1 transcription factor in esophageal carcinoma defective of the p53 pathway.
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发表时间：
2019
影响因子：
5.3
通讯作者：
Boya Zhong;M. Shingyoji;Michiko Hanazono;Thao T. T. Nguyen-Thao-T.-T.-Nguyen-2140461207;T. Morinaga;Y. Tada;K. Hiroshima;H. Shimada
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作者：
Boya Zhong;M. Shingyoji;Michiko Hanazono;Thao T. T. Nguyen-Thao-T.-T.-Nguyen-2140461207;T. Morinaga;Y. Tada;K. Hiroshima;H. Shimada
恢复p53功能是食管癌的治疗策略之一，因为食管癌常存在p53通路缺陷。我们检测了CP-31398可能增加野生型p53的表达或将突变p53转化为野生型的影响。我们用9种不同p53基因型的人食管鳞癌细胞，检测了cp -31398处理细胞中p53及相关分子的表达情况。顺铂是一种DNA损伤剂，可诱导PARP和caspase-3的裂解，但p53水平未升高，表明p53下游通路在这些细胞中被破坏。CP-31398诱导生长迟缓，但细胞毒性作用与p53基因型无关。CP-31398以细胞依赖的方式影响p53及其下游分子的表达，但在转录水平上不断增加p21的表达，而降低YY1的表达。siRNA敲低实验表明，cp -31398介导的p21上调与p53表达无关，而与YY1表达相关。我们还发现，cp -31398诱导的细胞周期变化，包括G2/M群体的增加，可归因于p21的上调。这些数据共同表明，CP-31398通过调控YY1增强内源性p21水平，诱导细胞周期变化，YY1是CP-31398在p53功能失调细胞中的新靶点。
Restoration of p53 functions is one of the therapeutic strategies for esophageal carcinoma which is often defective of the p53 pathway. We examined effects of CP-31398 which potentially increased expression of wild-type p53 or converted mutated p53 to the wild-type. We used 9 kinds of human squamous esophageal carcinoma cells with different p53 genotypes and examined expression of p53 and the related molecules in CP-31398-treated cells. Cisplatin, a DNA damaging agent, induced cleavages of PARP and caspase-3 without increase of p53 levels, indicating that the p53 down-stream pathway was disrupted in these cells. CP-31398 induced growth retardation but the cytotoxic effects were irrelevant to p53 genotype. CP-31398 influenced expression of p53 and the downstream molecules in a cell-dependent manner, but constantly increased p21 expression at the transcriptional level with decreased YY1 expression. Knockdown experiments with siRNA demonstrated that the CP-31398-mediated p21 up-regulation was unrelated with p53 expression but was associated with YY1 expression. We also showed that CP-31398-induced cell cycle changes including increase of G2/M populations was attributable to the up-regulated p21. These data collectively indicated that CP-31398 augmented endogenous p21 levels and induced cell cycle changes through regulation of YY1, and that YY1 was a novel target of CP-31398 in p53 dysfunctional cells.