{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T09:01:55Z","timestamp":1778058115335,"version":"3.51.4"},"reference-count":28,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,5,8]],"date-time":"2019-05-08T00:00:00Z","timestamp":1557273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["CMU107-N-07"],"award-info":[{"award-number":["CMU107-N-07"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Ministry of Science and Technology","award":["102-2320-B-038-039-MY3"],"award-info":[{"award-number":["102-2320-B-038-039-MY3"]}]},{"name":"the Health and welfare surcharge of tobacco products","award":["MOHW107-TDU-B-212-114014"],"award-info":[{"award-number":["MOHW107-TDU-B-212-114014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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%\u201320% 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.<\/jats:p>","DOI":"10.3390\/ijms20092271","type":"journal-article","created":{"date-parts":[[2019,5,9]],"date-time":"2019-05-09T08:19:59Z","timestamp":1557389999000},"page":"2271","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells"],"prefix":"10.3390","volume":"20","author":[{"given":"Shu-Huey","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jyh-Ming","family":"Chow","sequence":"additional","affiliation":[{"name":"Department of Hemato-Oncology, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao-Yu","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Shuang Ho Hospital, Taipei Meidcal University, New Taipei City 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2901-2681","authenticated-orcid":false,"given":"Chun-Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu 30068, Taiwan"},{"name":"Bioinformatics Center, Institute for Chemical Research, Kyoto University, Kyoto 611-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai-Wen","family":"Hsu","sequence":"additional","affiliation":[{"name":"Graduate Institute of New Drug Development and Biomedical Sciences, China Medical University, Taichung 40402, Taiwan"},{"name":"Research Center for Tumor Medical Science, China Medical University, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Shyang","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory, Shuang Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Ming","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0854-1170","authenticated-orcid":false,"given":"Beished M.","family":"Shabangu","sequence":"additional","affiliation":[{"name":"School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Hwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory, Shuang Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan"},{"name":"School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Ph.D. Program in Medicine Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"TMU Research Center of Cancer Translational Medicine, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mukaida, N., Tanabe, Y., and Baba, T. (2017). Chemokines as a Conductor of Bone Marrow Microenvironment in Chronic Myeloid Leukemia. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081824"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1002\/1878-0261.12186","article-title":"Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK-ERK and NF-kappaB pathways in a model of chronic myeloid leukemia","volume":"12","author":"Chorzalska","year":"2018","journal-title":"Mol. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9409","DOI":"10.3892\/mmr.2017.7835","article-title":"Semirandom mutagenesis profile of BCRABL during imatinib resistance acquirement in K562 cells","volume":"16","author":"Dong","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Eckschlager, T., Plch, J., Stiborova, M., and Hrabeta, J. (2017). Histone Deacetylase Inhibitors as Anticancer Drugs. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071414"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.molcel.2010.01.042","article-title":"Highly compacted chromatin formed in vitro reflects the dynamics of transcription activation in vivo","volume":"38","author":"Li","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5415","DOI":"10.1038\/onc.2013.482","article-title":"The role of p21(waf1\/cip1) and p27(Kip1) in HDACi-mediated tumor cell death and cell cycle arrest in the Emu-myc model of B-cell lymphoma","volume":"33","author":"Newbold","year":"2014","journal-title":"Oncogene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1007\/s00432-016-2229-x","article-title":"Histone deacetylase inhibitors induce proteolysis of activated CDC42-associated kinase-1 in leukemic cells","volume":"142","author":"Mahendrarajah","year":"2016","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Hsu, K.W., Huang, C.Y., Tam, K.W., Lin, C.Y., Huang, L.C., Lin, C.L., Hsieh, W.S., Chi, W.M., Chang, Y.J., and Wei, P.L. (2018). The Application of Non-Invasive Apoptosis Detection Sensor (NIADS) on Histone Deacetylation Inhibitor (HDACi)-Induced Breast Cancer Cell Death. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020452"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.biopha.2018.01.045","article-title":"Co-targeting poly(ADP-ribose) polymerase (PARP) and histone deacetylase (HDAC) in triple-negative breast cancer: Higher synergism in BRCA mutated cells","volume":"99","author":"Marijon","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.biopha.2017.04.037","article-title":"Chidamide in FLT3-ITD positive acute myeloid leukemia and the synergistic effect in combination with cytarabine","volume":"90","author":"Li","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.suronc.2018.07.015","article-title":"Histone deacetylase inhibitors in hepatocellular carcinoma: A therapeutic perspective","volume":"27","author":"Tsilimigras","year":"2018","journal-title":"Surg. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ungerstedt, J.S. (2018). Epigenetic Modifiers in Myeloid Malignancies: The Role of Histone Deacetylase Inhibitors. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103091"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"18252","DOI":"10.3390\/ijms160818252","article-title":"The Histone Deacetylase Inhibitor BML-210 Influences Gene and Protein Expression in Human Promyelocytic Leukemia NB4 Cells via Epigenetic Reprogramming","volume":"16","author":"Borutinskaite","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1515\/hsz-2016-0307","article-title":"Valproic acid (VPA) enhances cisplatin sensitivity of non-small cell lung cancer cells via HDAC2 mediated down regulation of ABCA1","volume":"398","author":"Chen","year":"2017","journal-title":"Biol. Chem"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1158\/1535-7163.MCT-16-0588","article-title":"Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome","volume":"16","author":"Raynal","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lin, C.L., Tsai, M.L., Lin, C.Y., Hsu, K.W., Hsieh, W.S., Chi, W.M., Huang, L.C., and Lee, C.H. (2019). HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020454"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.mrfmmm.2013.07.002","article-title":"Mammalian DNA repair: HATs and HDACs make their mark through histone acetylation","volume":"750","author":"Gong","year":"2013","journal-title":"Mutat. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1007\/s00018-013-1295-3","article-title":"Metabolism, longevity and epigenetics","volume":"70","author":"Cosentino","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s13148-017-0358-y","article-title":"Epi-drugs in combination with immunotherapy: A new avenue to improve anticancer efficacy","volume":"9","author":"Mazzone","year":"2017","journal-title":"Clin. Epigenet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chen, Y., Tsai, Y.H., and Tseng, S.H. (2017). HDAC Inhibitors and RECK Modulate Endoplasmic Reticulum Stress in Tumor Cells. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020258"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1073\/pnas.0307708100","article-title":"Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1","volume":"101","author":"Gui","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6817","DOI":"10.1074\/jbc.M007372200","article-title":"Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST\/kiaa0071 and Mta-L1","volume":"276","author":"Humphrey","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3835783","DOI":"10.1155\/2018\/3835783","article-title":"CRISPR\/Cas9 Genome Editing of Epidermal Growth Factor Receptor Sufficiently Abolished Oncogenicity in Anaplastic Thyroid Cancer","volume":"2018","author":"Huang","year":"2018","journal-title":"Dis. Markers"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"336","DOI":"10.3389\/fncel.2017.00336","article-title":"Nicotinic Acetylcholine Receptor Subtype Alpha-9 Mediates Triple-Negative Breast Cancers Based on a Spontaneous Pulmonary Metastasis Mouse Model","volume":"11","author":"Huang","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1111\/cas.12965","article-title":"Combination of panobinostat with ponatinib synergistically overcomes imatinib-resistant CML cells","volume":"107","author":"Matsuda","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1093\/jnci\/djq300","article-title":"Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells","volume":"102","author":"Lee","year":"2010","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Tu, S.H., Hsieh, Y.C., Huang, L.C., Lin, C.Y., Hsu, K.W., Hsieh, W.S., Chi, W.M., and Lee, C.H. (2017). A rapid and quantitative method to detect human circulating tumor cells in a preclinical animal model. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3419-x"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1126\/science.1247005","article-title":"Genome-scale CRISPR-Cas9 knockout screening in human cells","volume":"343","author":"Shalem","year":"2014","journal-title":"Science"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/9\/2271\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:50:01Z","timestamp":1760187001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/9\/2271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,8]]},"references-count":28,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["ijms20092271"],"URL":"https:\/\/doi.org\/10.3390\/ijms20092271","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,8]]}}}