Disrupting the interaction between a p53 gain ‐of‐function mutant and the transcriptional co‐activator PC4 reverses drug resistance in cancer cells

In a tumor cell harboring the gain-of-function mutant R273Hp53, the mutant p53 protein is recruited to the promoters of theMDR1 andUBE2C multidrug resistance-associated genes, assisted by the chromatin-associated protein PC4. This recruitment upregulates both genes. A peptide designed to disrupt the R273Hp53 –PC4 interaction, downregulatesMDR1 andUBE2C expression, sensitizing the cells to doxorubicin. This suggests that the PC4 –R273Hp53 interaction is a promising target for reducing drug resistance. 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 resistanc e in tumors.
Source: FEBS Letters - Category: Biochemistry Authors: Tags: Research Article Source Type: research