TY - JOUR
T1 - HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells
AU - Chen, Shu Huey
AU - Chow, Jyh Ming
AU - Hsieh, Yao Yu
AU - Lin, Chun Yu
AU - Hsu, Kai Wen
AU - Hsieh, Wen Shyang
AU - Chi, Wei Ming
AU - Shabangu, Beished M.
AU - Lee, Chia Hwa
N1 - Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
KW - CML
KW - CRISPR/Cas9
KW - histone deacetylase inhibitor
KW - imatinib
KW - imatinib-resistant
KW - Acetylation/drug effects
KW - Histone Deacetylase 2/genetics
KW - Humans
KW - Apoptosis/drug effects
KW - Drug Resistance, Neoplasm/drug effects
KW - Neoplastic Stem Cells/drug effects
KW - Gene Knockout Techniques
KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
KW - CRISPR-Cas Systems/genetics
KW - Imatinib Mesylate/adverse effects
KW - K562 Cells
KW - Histone Deacetylase Inhibitors/pharmacology
KW - Fusion Proteins, bcr-abl/antagonists & inhibitors
KW - Histone Deacetylase 1/genetics
KW - Panobinostat/pharmacology
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U2 - 10.3390/ijms20092271
DO - 10.3390/ijms20092271
M3 - Article
C2 - 31071955
AN - SCOPUS:85065877466
SN - 1661-6596
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 9
M1 - 2271
ER -