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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Bcr-Abl-Independent Imatinib-Resistant K562 Cells Show Aberrant Protein Acetylation and Increased Sensitivity to Histone Deacetylase Inhibitors

Department of Biochemistry and Research Center for Ischemic Tissue Regeneration, Pusan National University School of Medicine, Busan, South Korea (S.M.L., J.H.B., M.J.K., B.S.C., C.D.K., S.H.K.); Department of Internal Medicine and Medical Research Institutes and Busan Regional Cancer Center, Pusan National University Hospital, Busan, South Korea (M.K.L., C.D.K., S.H.K.); Otolaryngology Department, Busan Medical Center, Busan, South Korea (H.S.L.); and Department of Microbiology, College of Natural Sciences, Chang Won National University, Chang Won, South Korea (D.W.K.)

Bcr-Abl-independent signaling pathways are known to be involved in imatinib resistance in some patients with chronic myelogenous leukemia (CML). In this study, to find new targets for imatinib-resistant CML displaying loss of Bcr-Abl kinase target dependence, we isolated imatinib-resistant variants, K562/R1, K562/R2, and K562/R3, which showed profound declines of Bcr-Abl levels and its tyrosine kinase activity, from K562 cells. Importantly, the imatinib resistance mechanism in these variants also included aberrant acetylation of nonhistone proteins such as p53, Ku70, and Hsp90 that was due to upregulation of histone deacetylases (HDACs) and down-regulation of histone acetyltransferase (HAT). In comparison with K562 cells, the imatinib-resistant variants showed up-regulation of HDAC1, -2, and -3 (class I HDACs) and class III SIRT1 and down-regulation of CBP/p300 and PCAF with HAT activity, and thereby p53 and cytoplasmic Ku70 were aberrantly acetylated. In addition, these were associated with down-regulation of Bax and up-regulation of Bcl-2. In contrast, the class II HDAC6 level was significantly decreased, and this was accompanied by an increase of Hsp90 acetylation in the imatinib-resistant variants, which was closely associated with loss of Bcr-Abl. These results indicate that alteration of the normal balance of HATs and HDACs leads to deregulated acetylation of Hsp90, p53, and Ku70 and thereby leads to imatinib resistance, suggesting the importance of the acetylation status of apoptosis-related nonhistone proteins in Bcr-Abl-independent imatinib resistance. We also revealed that imatinib-resistant K562 cells were more sensitive to suberoylanilide hydroxamic acid, an HDAC inhibitor, than K562 cells. These findings may have implications for HDAC as a molecular target in imatinib-resistant leukemia cells.

Address correspondence to: Dr. Sun Hee Kim, Department of Biochemistry, College of Medicine, Pusan National University, Pusan 602-739, South Korea. E-mail: ksh7738{at}pusan.ac.kr