Activation of ABCC Genes by Cisplatin Depends on the CoREST Occurrence at Their Promoters in A549 and MDA-MB-231 Cell Lines

SIMPLE SUMMARY: Cisplatin resistance is a common issue that affects patients with a variety of cancers who are treated with this drug. In this research, we present a novel epigenetic mechanism that controls the expression of ABC-family transporters, which are involved in multidrug resistance. We report that the CoREST complex may be a key factor that determines the transcription of ABC transporters in non-small cell lung and triple-negative breast cancer cells (A549 and MDA-MB-231, respectively) treated with cisplatin. By occupying gene promoters, this multi-subunit repressor prevents both an EP300-dependent increase in ABCC transcription induced by the alkylating drug and gene overexpression in cisplatin-resistant phenotypes. Moreover, the CoREST-free promoter of ABCC10 responds to cisplatin with EP300-mediated gene activation, which is only possible in p53-proficient cells. ABSTRACT: 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 ABCC 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 ABCC10 in cisplatin-resistant phenotypes was caused by the activity of EP300 that was enriched at the ABCC10 promoter in drug-treated cells. Cisplatin-induced and EP300-dependent transcriptional activation of ABCC10 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 ABCC genes by EP300 occurs once their promoters are devoid of the CoREST complex.