HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells

Since imatinib (Glivec or Gleevec) has been used to target the BCR-ABL fusion protein, chronic myeloid leukemia (CML) has become a manageable chronic disease with long-term survival. However, 15%-20% of CML patients ultimately develop resistance to imatinib and then progress to an accelerated phase...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 20; no. 9; p. 2271
Main Authors:	Chen, Shu-Huey, Chow, Jyh-Ming, Hsieh, Yao-Yu, Lin, Chun-Yu, Hsu, Kai-Wen, Hsieh, Wen-Shyang, Chi, Wei-Ming, Shabangu, Beished M, Lee, Chia-Hwa
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 08-05-2019 MDPI
Subjects:	Abl protein Acetylation Acetylation - drug effects AKT protein Amino acids Apoptosis Apoptosis - drug effects BCR protein Bioluminescence Blast crisis Blast resistance Cancer therapies Cell cycle Cell fusion Cell proliferation Chromatin remodeling Chromosomes CML CRISPR-Cas Systems - genetics CRISPR/Cas9 Deacetylation Deoxyribonucleic acid Disruption DNA Drug Resistance, Neoplasm - drug effects Drugs Epigenetics FDA approval Flow cytometry Fusion protein Fusion Proteins, bcr-abl - antagonists & inhibitors Fusion Proteins, bcr-abl - genetics Gene expression Gene Knockout Techniques Histone deacetylase Histone Deacetylase 1 - genetics Histone Deacetylase 2 - genetics histone deacetylase inhibitor Histone Deacetylase Inhibitors - pharmacology Histones Humans Imatinib Imatinib Mesylate - adverse effects Imatinib Mesylate - pharmacology imatinib-resistant Investigations K562 Cells Kinases Leukemia Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology MAP kinase Neoplastic Stem Cells - drug effects Nonhistone proteins Nucleotide sequence Panobinostat - pharmacology Protein-tyrosine kinase Proteins Targeted cancer therapy Transcription factors Tyrosine imatinib-resistant imatinib CML CRISPR/Cas9 histone deacetylase inhibitor
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Summary:	Since imatinib (Glivec or Gleevec) has been used to target the BCR-ABL fusion protein, chronic myeloid leukemia (CML) has become a manageable chronic disease with long-term survival. However, 15%-20% of CML patients ultimately develop resistance to imatinib and then progress to an accelerated phase and eventually to a blast crisis, limiting treatment options and resulting in a poor survival rate. Thus, we investigated whether histone deacetylase inhibitors (HDACis) could be used as a potential anticancer therapy for imatinib-resistant CML (IR-CML) patients. By applying a noninvasive apoptosis detection sensor (NIADS), we found that panobinostat significantly enhanced cell apoptosis in K562 cells. A further investigation showed that panobinostat induced apoptosis in both K562 and imatinib-resistant K562 (IR-K562) cells mainly via H3 and H4 histone acetylation, whereas panobinostat targeted cancer stem cells (CSCs) in IR-K562 cells. Using CRISPR/Cas9 genomic editing, we found that HDAC1 and HDAC2 knockout cells significantly induced cell apoptosis, indicating that the regulation of HDAC1 and HDAC2 is extremely important in maintaining K562 cell survival. All information in this study indicates that regulating HDAC activity provides therapeutic benefits against CML and IR-CML in the clinic.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms20092271