CBP/p300 Bromodomain Inhibitor–I–CBP112 Declines Transcription of the Key ABC Transporters and Sensitizes Cancer Cells to Chemotherapy Drugs

Abstract

The high expression of some ATP-binding cassette (ABC) transporters is linked to multidrug resistance in cancer cells. We aimed to determine if I-CBP112, which is a CBP/p300 bromodomain inhibitor, altered the vulnerability of the MDA-MB-231 cell line to chemotherapy drugs, which are used in neoadjuvant therapy in patients with triple negative breast cancer (TNBC). MDA-MB-231 cells represent TNBC, which is negative for the expression of estrogen and progesterone receptors and HER2 protein. An I-CBP112-induced decrease in the expression of all the studied ABCs in the breast, but also in the lung (A549), and hepatic (HepG2) cancer cell lines was associated with increased accumulation of doxorubicin, daunorubicin, and methotrexate inside the cells as well as considerable cell sensitization to a wide range of chemotherapeutics. Gene promoters repressed by I-CBP112 in MDA-MB-231 cells, such as ABCC1 and ABCC10, were characterized by enhanced nucleosome acetylation and, simultaneously, by considerably lower trimethylation in the transcription-promoting form of H3K4me3. The CBP/p300 bromodomain inhibitor induced the recruitment of LSD1 to the gene promoters, and the inhibition of this demethylase in the presence of I-CBP112 prevented the repression of ABCC1 and ABCC10 and, to a considerable extent, cancer cells’ sensitization to drugs. In conclusion, the CBP/p300 bromodomain inhibitor I-CBP112 can be considered as a potent anti-multidrug-resistance agent, capable of repressing key ABC transporters responsible for drug efflux in various cancer types.

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

“…These findings underline the necessity of a deep understanding of epigenetic landscapes, which drives the formation of multi-drug-resistant phenotypes in human tumors, to successfully target drug-resistant phenotypes. In a relatively recent report, EP300 bromodomain inhibitor, I-CBP112, was shown to decrease the expression of ABCC1 , ABCC3 , ABCC4 , ABCC5 , and ABCC10 transporters in MDA-MB-231 cells [ 27 ]. Similarly, knockdown of EP300 decreased the expression of ABCC1 and ABCG2 in TNBC cells, thereby suggesting the crucial role of the acetyltransferase interaction with chromatin on the high transcription efficacy of some ABC gene family members associated with neoplastic transformation.…”

“…In turn, increased activity of EP300 correlated with enhanced resistance to a variety of compounds in prostate cancer [ 43 , 44 , 45 ]. In breast cancer cells, inhibition of acetyltransferase sensitized cancer cells to a variety of chemotherapeutics, by impeding drug efflux and increasing drug accumulation [ 27 ].…”

“…Moreover, the effect of simultaneous deficiency of two or more HDACs activity may vary from inhibition of a single enzyme. The other CoREST complex member, LSD1, was reported to repress ABCC1 and ABCC10 gene expression upon inhibition of EP300 in the triple-negative breast cancer cell line MDA-MB-231 [ 27 ]. Bearing in mind that the promoter of ABCC10 is not repressed by LSD1 and HDACs in MDA-MB-231 and A549 cells, nor enriched in CoREST protein, the deficiency of EP300 activity seems to recruit histone demethylase or the entire CoREST complex to the ABCC10 gene regulatory element.…”

“…These findings suggest the possible implication of p53-EP300 mutual interdependence in the development of multi-drug resistance. Particularly, EP300 bromodomain inhibitor, I-CBP112, recently emerged as an ABC gene repressor in p53 wild-type cell lines [ 27 ].…”

“…Similar to HDACs, LSD1 (lysine-specific demethylase—also known as KDM1A) is capable of suppressing ABC-family gene expression upon deficiency of EP300 activity. Inhibition of LSD1 counteracts suppression of ABCC1 and ABCC10 expression caused by EP300 bromodomain inhibitor [ 27 ].…”