Az MDR1 gén kromatin szerkezetének tanulmányozása gyógyszerérzékeny és gyógyszerrezisztens humán sejtekben

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Our results indicate that the drug resistant MCF7-KCR cell line uses multiple mechanisms that ensure elevated MDR1 expression. These mechanisms include gene amplifications and epigenetic alterations. Gene expression is associated with highly increased acetylation level of H3K9 lysine residue around the transcriptional start site in the drug resistant cells. Gene induction in the drug sensitive cells is also accompanied with acetylation of H3K9 in the promoter region. p300 and PCAF regulate MDR1 basal transcriptional activity in drug sensitive cells. In the drug resistant cells PCAF and GCN5 substitute each other in maintaining the elevated expression of MDR1 and they may be responsible for generating the elevated H3K9 acetylation pattern at the MDR1 TSS. Generally, histone acetylation level is positively correlated with transcriptional activity. Our results demonstrate that active gene expression correlates with the increased acetylation level of only specific lysine residues. However, acetylation of specific lysines not certainly results in additional gene activity. Importantly, despite a change of gene expression histone acetylation level in the gene chromatin can be unaltered. Our data suggest that repeated exposure to chemotherapy may result in deregulated histone acetylation. Our findings are valuable for the understanding of the role of histone modifications in cancer.

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