Journal article
Histone deacetylase inhibitors target DNA replication regulators and replication stress in Ewing sarcoma cells
Cancer research communications, Vol.5(6), pp.1034-1048
06/01/2025
DOI: 10.1158/2767-9764.CRC-25-0058
PMCID: PMC12202856
PMID: 40478628
Abstract
Histone deacetylases (HDAC) regulate diverse pathways in cancer cells. Previously, we identified that Ewing sarcoma tumors, which are caused by a translocation between the EWSR1 and FLI1 genes (EWS::FLI1), are sensitive to drugs that target DNA replication, including the RRM1 and RRM2 subunits of ribonucleotide reductase (RNR), and the ATR-CHK1-WEE1 signaling pathway. In this study, we identified that multiple HDAC inhibitors, including fimepinostat, romidepsin and panobinostat, downregulate the levels of the RRM1, RRM2, CHK1, and WEE1 proteins in Ewing sarcoma cells, and impair DNA replication. Moreover, transcriptome analyses identified that HDAC inhibitors downregulate the expression of multiple components of the pre-replication complex (pre-RC), including the MCM2-7 proteins and CDT1, that are essential for genomic DNA replication. Additionally, proteomic studies identified that HDAC inhibitors also downregulate the level of the BRD4 protein, a BET bromodomain protein that regulates both the transcriptional program of the EWS::FLI1 oncoprotein and DNA replication. Overall, these results provide novel insight into the molecular mechanisms by which HDAC inhibitors target cancer cells, regulate DNA replication, and inhibit the cellular response to DNA replication stress.
Details
- Title: Subtitle
- Histone deacetylase inhibitors target DNA replication regulators and replication stress in Ewing sarcoma cells
- Creators
- Stacia L Koppenhafer - University of Iowa, Iowa City, IA, United StatesElizabeth L Geary - University of IowaMary V Thomas - University of Iowa, Iowa City, IA, United StatesEmma E Croushore - Cold Spring Harbor LaboratoryJessica A O Zimmerman - University of IowaJenna M Gedminas - University of IowaDawn E Quelle - University of Iowa, Iowa City, IA, United StatesRebecca D Dodd - University of Iowa, Iowa City, IA, United StatesDavid J Gordon - University of Iowa, Iowa City, IA, United States
- Resource Type
- Journal article
- Publication Details
- Cancer research communications, Vol.5(6), pp.1034-1048
- DOI
- 10.1158/2767-9764.CRC-25-0058
- PMID
- 40478628
- PMCID
- PMC12202856
- NLM abbreviation
- Cancer Res Commun
- ISSN
- 2767-9764
- eISSN
- 2767-9764
- Publisher
- AMER ASSOC CANCER RESEARCH
- Grant note
- Pediatric Cancer Research FoundationStead Fund for Leadership Development & Innovation in Pediatric Medicine, Sammy's Superheroes, Cal's AngelsHyundai Hope on WheelsCharlie Landers FoundationNIH: R37-CA217910, P30CA086862 NCIUniversity of Iowa Carver College of Medicine: NCI P30CA086862
D.J. Gordon is supported by the Matt Morrell and Natalie Sanchez Pediatric Cancer Research Foundation, the Stead Fund for Leadership Development & Innovation in Pediatric Medicine, Sammy's Superheroes, Cal's Angels, Unravel Pediatric Cancer, Hyundai Hope on Wheels, the Sarah Waul Family Fund, the Charlie Landers Foundation, the Dominic Gentile DVM Sarcoma Research Fund, and NIH Grant R37-CA217910. This work was also supported by a grant (P30CA086862) from the NCI, administered through the Holden Comprehensive Cancer Center at the University of Iowa. The authors would like to acknowledge the use of the University of Iowa Flow Cytometry Facility and the DNA sequencing facility (Genomics Division of the Iowa Institute of Human Genetics), which are supported, in part, by the University of Iowa Carver College of Medicine and the Holden Comprehensive Cancer Center (NCI P30CA086862).
- Language
- English
- Electronic publication date
- 06/06/2025
- Date published
- 06/01/2025
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Pathology; Medical Genetics and Genomics; Hematology/Oncology; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984826346302771
Metrics
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