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A novel histone deacetylase inhibitor MPT0L184 dysregulates cell-cycle checkpoints and initiates unscheduled mitotic signaling

Chang, Ting-Yu and Nepali, Kunal and Chen, Yi-Ying and Yang, Yu-Chen S. H. and Hsu, Kai-Cheng and Yen, Yun and Pan, Shiow-Lin and Liou, Jing-Ping and Lee, Sung-Bau (2021) A novel histone deacetylase inhibitor MPT0L184 dysregulates cell-cycle checkpoints and initiates unscheduled mitotic signaling. Biomedicine & Pharmacotherapy, 138 . Art. No. 111485. ISSN 0753-3322. doi:10.1016/j.biopha.2021.111485. https://resolver.caltech.edu/CaltechAUTHORS:20210329-151219066

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Abstract

Aberrant alteration of epigenetic information disturbs chromatin structure and gene function, thereby facilitating cancer development. Several drugs targeting histone deacetylases (HDACs), a group of epigenetic enzymes, have been approved for treating hematologic malignancies in the clinic. However, patients who suffer from solid tumors often respond poorly to these drugs. In this study, we report a selective entinostat derivative, MPT0L184, with potent cancer-killing activity in both cell-based and mouse xenograft models. A time-course analysis of cell-cycle progression revealed that MPT0L184 treatment elicited an early onset of mitosis but prevented the division of cells with duplicated chromosomes. We show that MPT0L184 possessed potent inhibitory activity toward HDAC1 and 2, and its HDAC-inhibitory activity was required for initiating premature mitotic signaling. HDAC inhibition by MPT0L184 reduced WEE1 expression at the transcription level. In addition, MPT0L184 treatment also downregulated ATR-mediated CHK1 phosphorylation independent of HDAC inhibition. Furthermore, gastric cancer cells resistant to HDAC inhibitors were vulnerable to MPT0L184. Taken together, our study discovers MPT0L184 as a novel HDAC inhibitor that can trigger premature mitosis and potentially counteract drug resistance of cancers.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.biopha.2021.111485DOIArticle
ORCID:
AuthorORCID
Yen, Yun0000-0003-0815-412X
Additional Information:© 2021 The Authors. Published by Elsevier Masson SAS. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 11 December 2020, Revised 8 March 2021, Accepted 9 March 2021, Available online 16 March 2021. We thank Dr. Sun Young Rha (Songdang Institute for Cancer Research) for providing the YCC cell lines, and Drs. Li-Jung Juan (Genomics Research Center, Academia Sinica) and Sheau-Yann Shieh (Institute of Biomedical Sciences, Academia Sinica) for providing essential antibodies and reagents. We also appreciate Nian-Zhe Lee and Dan-Qi Yang (Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University (TMU)) for assistance and the technical support provided by the Core Facilities of TMU and Academia Sinica. We acknowledge the academic and science graphic illustration service provided by Research Promotion Center of TMU. Financial support: This research was supported by the Taiwan Ministry of Science and Technology [MOST 107-2113-M-038-001] to J.-P. Liou, and Taipei Medical University [108-3805-020-400] and the Taiwan Ministry of Education [4151B-(106)] to S.-B. Lee. Data sharing: The authors declare that all data supporting the findings of this study are available within the paper and its supplementary information files, or are available from the corresponding author upon reasonable request. CRediT authorship contribution statement: T.-Y. Chang: Formal analysis, Investigation, Visualization, Writing - original draft. K. Nepali: Resources, Writing - review & editing. Y.-Y. Chen: Formal analysis, Investigation. Y.-C.S.H. Yang: Investigation. K.-C. Hsu: Investigation. Y. Yen: Conceptualization, Project administration, Supervision, Writing - review & editing. S.-L. Pan: Supervision, Visualization, Writing - review & editing. J.-P. Liou: Conceptualization, Funding acquisition, Resources, Supervision, Writing - review & editing. S.-B. Lee: Conceptualization, Funding acquisition, Supervision, Writing - original draft and editing. The authors declare no potential conflicts of interest.
Funders:
Funding AgencyGrant Number
Ministry of Science and Technology (Taipei)MOST 107-2113-M-038-001
Taipei Medical University108-3805-020-400
Ministry of Education (Taipei)4151B-(106)
Subject Keywords:Histone deacetylases (HDACs); MPT0L184, Checkpoint kinases; Cyclin-dependent kinases (CDKs); Premature mitosis; Drug resistance
DOI:10.1016/j.biopha.2021.111485
Record Number:CaltechAUTHORS:20210329-151219066
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210329-151219066
Official Citation:Ting-Yu Chang, Kunal Nepali, Yi-Ying Chen, Yu-Chen S.H. Yang, Kai-Cheng Hsu, Yun Yen, Shiow-Lin Pan, Jing-Ping Liou, Sung-Bau Lee, A novel histone deacetylase inhibitor MPT0L184 dysregulates cell-cycle checkpoints and initiates unscheduled mitotic signaling, Biomedicine & Pharmacotherapy, Volume 138, 2021, 111485, ISSN 0753-3322, https://doi.org/10.1016/j.biopha.2021.111485. (https://www.sciencedirect.com/science/article/pii/S0753332221002705)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108575
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Mar 2021 22:57
Last Modified:30 Mar 2021 22:57

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