Abstract
Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. In this study, we further investigated the biological function of HDAC5 in cancer cells. We found HDAC5 is associated with actively replicating pericentric heterochromatin during late S phase. We demonstrated that specific depletion of HDAC5 by RNA interference resulted in profound changes in the heterochromatin structure and slowed down ongoing replication forks. This defect in heterochromatin maintenance and assembly are sensed by DNA damage checkpoint pathways, which triggered cancer cells to autophagy and apoptosis, and arrested their growth both in vitro and in vivo. Finally, we also demonstrated that HDAC5 depletion led to enhanced sensitivity of DNA to DNA-damaging agents, suggesting that heterochromatin de-condensation induced by histone HDAC5 silencing may enhance the efficacy of cytotoxic agents that act by targeting DNA in vitro. Together, these results highlighted for the first time an unrecognized link between HDAC5 and the maintenance/assembly of heterochromatin structure, and demonstrated that its specific inhibition might contribute to increase the efficacy of DNA alteration-based cancer therapies in clinic.
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11 August 2025
An Editorial Expression of Concern to this paper has been published: https://doi.org/10.1038/s41418-025-01556-x
Abbreviations
- Akt:
-
protein kinase B
- Bax:
-
Bcl-2-associated X
- Bcl-2:
-
B-cell lymphoma 2
- BrdU:
-
5-bromo-2′-deoxyuridine
- CAM:
-
chorioallantoic membrane
- CDK:
-
cyclin-dependent kinase
- CDKi:
-
cyclin-dependent kinase inhibitor
- Chk1:
-
checkpoint kinase 1
- Chk2:
-
checkpoint kinase 2
- Cip1:
-
CDK-interacting protein 1
- CldU:
-
chlorodeoxyuridine
- DMEM:
-
Dulbecco's modified Eagle's medium
- DNMT1:
-
DNA methyltransferase 1
- DSBs:
-
double-strand breaks
- DTT:
-
dithiothreitol
- E2F1:
-
transcription factor E2F1
- FACS:
-
fluorescence-activated cell sorting
- FBS:
-
fetal bovine serum
- FDA:
-
Food and Drug Administration
- FITC:
-
fluorescein isothiocyanate
- γ-H2AX:
-
histone H2A.x phosphorylated on serine 139
- HDAC:
-
histone deacetylase
- HDACi:
-
histone deacetylase inhibitor
- HP-1:
-
heterochromatin protein 1
- HRP:
-
horseradish peroxidase
- HSC70:
-
heat-shock cognate 70-kDa protein
- IdU:
-
iododeoxyuridine
- kip1:
-
kinase-interacting protein 1
- LC3:
-
microtubule-associated protein 1A/1B-light chain 3
- MCM:
-
mini-chromosome maintenance protein
- MEK2:
-
MAPK/ERK kinase 2
- MNaseI:
-
micrococcal nuclease 1
- Mus81:
-
methyl methanesulfonate and ultraviolet-sensitive gene clone 81
- NuRD:
-
nucleosome-remodeling deacetylase complex
- ORC:
-
origin recognition complex
- PBS:
-
phosphate-buffered saline
- PCNA:
-
proliferating cell nuclear antigen
- PI:
-
propidium iodide
- PI3K:
-
phosphoinositide-3-kinase
- pRb:
-
retinoblastoma protein
- RNAi:
-
RNA interference
- SA-β-gal:
-
senescence-associated β-galactosidase
- SAHA:
-
suberoylanilide hydroxamic acid
- SDS:
-
sodium dodecyl sulfate
- siRNA:
-
small interfering RNA
- SIRT:
-
sirtuin
- TSA:
-
trichostatin A
- WST-1:
-
2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt
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Acknowledgements
This work was supported by grants from the National Fund for Scientific Research (FNRS) (Belgium), the Centre Anti-Cancéreux près de l’Université de Liège, the Fonds Léon Frédéricq, and TELEVIE. D Mottet and F Dequiedt are Research Associates at the National Fund for Scientific Research (FNRS). M Boxus is Postdoctoral Researcher at the FNRS. N Matheus is an FRIA Fellow. A Gonzalez is TELEVIE Fellow. We thank Dr D DiPaola for expert advice on the nascent-strand DNA abundance assay.
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Peixoto, P., Castronovo, V., Matheus, N. et al. HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells. Cell Death Differ 19, 1239–1252 (2012). https://doi.org/10.1038/cdd.2012.3
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DOI: https://doi.org/10.1038/cdd.2012.3
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