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

Autor: Mondal P; Department of Biophysics, Bose Institute, Kolkata, India., Roy KS; Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India., Bhagat SV; Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India., Singh S; Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India., Chattopadhyay A; Saroj Gupta Cancer Centre & Research Institute, Kolkata, India., Ghosh DD; Saroj Gupta Cancer Centre & Research Institute, Kolkata, India., Kundu TK; Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India., Roychoudhury S; Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India., Roy S; Department of Biophysics, Bose Institute, Kolkata, India.
Jazyk: angličtina
Zdroj: FEBS letters [FEBS Lett] 2024 Jun; Vol. 598 (12), pp. 1532-1542. Date of Electronic Publication: 2024 Apr 25.
DOI: 10.1002/1873-3468.14890
Abstrakt: 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.
(© 2024 Federation of European Biochemical Societies.)
Databáze: MEDLINE
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