A novel histone deacetylase inhibitor MPT0L184 dysregulates cell-cycle checkpoints and initiates unscheduled mitotic signaling
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.
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.Attached Files
Published - 1-s2.0-S0753332221002705-main.pdf
Supplemental Material - 1-s2.0-S0753332221002705-mmc1.pdf
Supplemental Material - 1-s2.0-S0753332221002705-mmc2.pdf
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Additional details
- Eprint ID
- 108575
- Resolver ID
- CaltechAUTHORS:20210329-151219066
- MOST 107-2113-M-038-001
- Ministry of Science and Technology (Taipei)
- 108-3805-020-400
- Taipei Medical University
- 4151B-(106)
- Ministry of Education (Taipei)
- Created
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2021-03-30Created from EPrint's datestamp field
- Updated
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2021-03-30Created from EPrint's last_modified field