Department of Biophysics, Bose Institute, Kolkata, India.
Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
FEBS Lett. 2024 Jun;598(12):1532-1542. doi: 10.1002/1873-3468.14890. Epub 2024 Apr 25.
PC4 is a chromatin-associated protein and transcriptional coactivator whose role in gene regulation by wild-type p53 is now well known. Little is known about the roles of PC4 in tumor cells bearing mutant p53 genes. We show that PC4 associates with one of the tumor-associated gain-of-function p53 mutants, R273H. This association drives its recruitment to two promoters, UBE2C and MDR1, known to be responsible for imparting aggressive growth and resistance to many drugs. Here, we introduced a peptide that disrupts the PC4-R273Hp53 interaction to tumor cells bearing the R273HTP53 gene, which led to a lowering of MDR1 expression and abrogation of drug resistance in a mutant-specific manner. The results suggest that the PC4-R273Hp53 interaction may be a promising target for reducing proliferation and drug resistance in tumors.
PC4 是一种与染色质相关的蛋白和转录共激活因子，其在野生型 p53 调控基因中的作用现在已经众所周知。然而，关于携带突变型 p53 基因的肿瘤细胞中 PC4 的作用知之甚少。我们发现 PC4 与一种肿瘤相关的获得性功能突变型 p53 蛋白，即 R273H，相互作用。这种相互作用促使 PC4 募集到两个启动子，UBE2C 和 MDR1，这两个启动子已知负责赋予肿瘤细胞侵袭性生长和对多种药物的耐药性。在这里，我们向携带 R273HTP53 基因的肿瘤细胞中引入了一种肽，该肽可以破坏 PC4-R273Hp53 相互作用，从而导致 MDR1 表达降低，并以突变型特异性的方式消除耐药性。这些结果表明，PC4-R273Hp53 相互作用可能是降低肿瘤增殖和耐药性的一个有前途的靶点。
