Sobczak Maciej, Strachowska Magdalena, Gronkowska Karolina, Robaszkiewicz Agnieszka
Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.
Cancers (Basel). 2022 Feb 11;14(4):894. doi: 10.3390/cancers14040894.
Although cisplatin-based therapies are common among anticancer approaches, they are often associated with the development of cancer drug resistance. This phenomenon is, among others, caused by the overexpression of ATP-binding cassette, membrane-anchored transporters (ABC proteins), which utilize ATP to remove, e.g., chemotherapeutics from intracellular compartments. To test the possible molecular basis of increased expression of ABCC subfamily members in a cisplatin therapy mimicking model, we generated two cisplatin-resistant cell lines derived from non-small cell lung cancer cells (A549) and triple-negative breast cancer cells (MDA-MB-231). Analysis of data for A549 cells deposited in UCSC Genome Browser provided evidence on the negative interdependence between the occurrence of the CoREST complex at the gene promoters and the overexpression of genes in cisplatin-resistant lung cancer cells. Pharmacological inhibition of CoREST enzymatic subunits-LSD1 and HDACs-restored gene responsiveness to cisplatin. Overexpression of CoREST-free in cisplatin-resistant phenotypes was caused by the activity of EP300 that was enriched at the promoter in drug-treated cells. Cisplatin-induced and EP300-dependent transcriptional activation of was only possible in the presence of p53. In summary, the CoREST complex prevents the overexpression of some multidrug resistance proteins from the ABCC subfamily in cancer cells exposed to cisplatin. p53-mediated activation of some genes by EP300 occurs once their promoters are devoid of the CoREST complex.
尽管基于顺铂的疗法在抗癌方法中很常见，但它们常常与癌症耐药性的产生相关。这种现象尤其由ATP结合盒膜锚定转运蛋白（ABC蛋白）的过表达引起，这些转运蛋白利用ATP将化疗药物等从细胞内区室清除。为了在模拟顺铂治疗的模型中测试ABCC亚家族成员表达增加的可能分子基础，我们从非小细胞肺癌细胞（A549）和三阴性乳腺癌细胞（MDA-MB-231）中生成了两种顺铂耐药细胞系。对UCSC基因组浏览器中A549细胞数据的分析提供了证据，表明顺铂耐药肺癌细胞中基因启动子处CoREST复合物的出现与基因过表达之间存在负相关。对CoREST酶亚基LSD1和HDACs的药理学抑制恢复了基因对顺铂的反应性。顺铂耐药表型中CoREST缺失的过表达是由药物处理细胞中启动子处富集的EP300的活性引起的。顺铂诱导的和EP300依赖的转录激活仅在p53存在时才可能发生。总之，CoREST复合物可防止暴露于顺铂的癌细胞中ABCC亚家族的一些多药耐药蛋白过表达。一旦某些基因的启动子没有CoREST复合物，EP300就会介导p53对这些基因的激活。
