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

Abstract

Simple SummaryDespite tremendous advances in cancer treatment, chemotherapy remains the first-line choice in many tumor types. The action of numerous chemotherapy drugs is limited by the occurrence of ABC proteins in cancer cell membranes, which remove medicines from cell compartments. In this paper, we show that one of bromodomain inhibitors, namely I-CBP112, was capable of repressing genes that are responsible for multidrug resistance in all three studied cancer cell lines. CBP/p300 bromodomain inhibitor allows for the higher drug accumulation inside cells and considerably potentiated drug effects. At the molecular level, I-CBP112 caused rearrangement of chromatin at the ABC gene promoters by inducing recruitment of LSD1, which removes transcription-promoting histone marks. I-CBP112 emerges as a promising compound to overcome ABC-dependent cancer drug resistance.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 with 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. 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.