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

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.

Intense endoplasmic reticulum stress (ERS) / IRE1α enhanced Oxaliplatin efficacy by decreased ABCC10 in colorectal cancer cells

“…Previous evidence showed other mechanisms that regulated ABCC10 expression. Transcriptional activation of ABCC10 gene was Cisplatin-induced and histone acetylases EP300-dependent in the presence of p53 [ 40 ]. As one of the most common epigenetic RNA modifications, N 6 -methyladenosine (m 6 A) modification mediated the expression of ABCC10.…”

Lysine-Specific Demethylase 1 Promises to Be a Novel Target in Cancer Drug Resistance: Therapeutic Implications

“…ATP-binding cassette transporter (ABC) proteins bound with membrane were involved in resistance to antitumor drugs by controlling drug efflux . Recently, two articles showed an association between LSD1 and ABC family members in drug resistance in BC. , LSD1 inhibition caused a decline in transcription of ABCC1 and ABCC10 induced by I-CBP112, so LSD1 was identified as a crucial repressor of ABC proteins . In addition, pharmacological inhibition of the CoREST enzymatic subunits (LSD1 and HDACs) recovered ABCC gene responsiveness to cisplatin …”

“…31 In addition, a research group clearly pointed out that responsiveness of ABCC gene to cisplatin was restored by restraining LSD1 and histone deacetylases (HDACs) (CoR-EST enzymatic subunits) in A549 cells. 63 Altogether, LSD1 not only plays a role in regulating cellular malignant biological properties but also functions at controlling the expression of genes related to drug efflux.…”

LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials

“…The same compounds gave downregulation of ERα, at both transcriptional and non-transcriptional levels, through modulation of miR-181a-5p expression ( Benedetti et al, 2019 ; Benedetti et al, 2021 ). The reduction of activity of LSD1, obtained by either pharmacological or genetic approach, could prevent resistance to antitumor agents in breast as well as other cancer models ( Lu et al, 2018 ; Sobczak et al, 2022 ). In blood cancers, various studies demonstrated the contribution of LSD1 to the onset and progression of AML ( Lokken and Zeleznik-Le, 2012 ).…”