Rola kompleksu SWI/SNF-EP300 w powstawaniu oporności komórek nowotworowych na chemioterapię

Abstract

Cancer remains a major global health problem and many tumours develop resistance to available therapies. Because drug resistance is often associated with genetic and epigenetic changes, targeting epigenetic regulators such as the histone acetyltransferase p300 and the SWI/SNF chromatin-remodelling complex may represent an effective therapeutic strategy.The aim of this thesis was to investigate the role of the SWI/SNF–p300 complex in the development of cancer drug resistance related to two mechanisms: overexpression of ABC transporters and activation of the DNA damage response pathway. In the first part of the study, I demonstrated that the chromatin remodelling ATPase BRG1 and the acetyltransferase p300 regulate the transcription of ABCC transporter genes (ABCC3, ABCC5 and ABCC10) in paclitaxel-resistant cancer cells. These lysosomal transporters were shown to sequester chemotherapeutic drugs such as doxorubicin and paclitaxel, reducing their cytotoxicity. Active promoters of these genes were enriched in BRG1, p300, HIF1A and activating histone marks. Pharmacological inhibition of SWI/SNF (PFI3), inhibition of p300 (C646), degradation of SWI/SNF ATPases, or silencing of HIF1A significantly increased drug toxicity by simultaneously reducing the expression of multiple ABC transporters. Bioinformatic analysis of clinical data further indicated that high expression of EP300, SMARCA4 and HIF1A may serve as prognostic markers of response to taxane-based chemotherapy in breast cancer. In the second part, I showed that cisplatin-induced activation of the ATM/ATR-Chk1/Chk2-p53 pathway enhances the association of p300 with chromatin and activates transcription of genes involved in DNA damage response. Inhibition of p300 or SWI/SNF reduced the expression of these genes and sensitised cancer cells to cisplatin. Overall, the results indicate that targeting SWI/SNF and p300 may reverse drug resistance and improve chemotherapy effectiveness.