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HDAC1 has intrinsic protease activity and regulates transcription through clipping histone H3 N-terminal tail

Cell Death & Differentiation (2025)Cite this article

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Abstract

Histone deacetylase 1 (HDAC1) has been mainly characterized as a factor removing acetyl groups from histone and non-histone proteins as well as inhibiting gene transcription. However, HDAC1 is also involved in positively regulating transcription of particular genes through as yet unknown mechanisms. Here we report the identification of an intrinsic protease activity residing in HDAC1 and capable of cleaving histone H3 between lysine 20 and alanine 21. Such HDAC1 protease activity toward H3 N-terminal tail (H3NT) depends on its stable association with nucleosomes and is required for bladder cancer cells to grow in an uncontrolled manner. Mechanistically, growth stimulatory genes are selectively activated by HDAC1-dependent H3NT proteolysis, and the levels of H3NT clipping are much higher in bladder cancer cells, serving as a cancer-specific chromatin signature. Moreover, artificial tethering of HDAC1 to target genes using CRISPR-dCas9 systems is sufficient for establishing H3NT proteolysis and achieving active transcriptional state in HDAC1-deficient cells, resulting in a higher proliferative capacity of cancer cells. Not only does this work establish HDAC1 as a new protease targeting H3NT, but our data also define a new mechanism underlying HDAC1-driven tumorigenesis by linking H3NT proteolysis to oncogenic gene expression program.

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Fig. 1: Proteolytic cleavage of histone H3NT catalyzed by HDAC1.
Fig. 2: Identification and characterization of proteolytically inactive HDAC1 mutants.
Fig. 3: HDAC1-nucleosome interaction dependent on HDAC1 C-terminal domain and H3NT.
Fig. 4: HDAC1-driven dysregulation of gene expression program in bladder cancer cells.
Fig. 5: Tumorigenic potential of bladder cancer cells promoted by HDAC1-dependent H3NT proteolysis.
Fig. 6: Targeted transactivation artificially generated by H3NT proteolysis in bladder cancer cells.

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Data availability

The gene expression array data has been deposited in the NCBI Gene Expression Omnibus (GEO) database under the GEO accession number GSE272621.

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Acknowledgements

We appreciate Ivetta Vorobyova at MIC (Molecular Imaging Center) USC for the performance of optical imaging (NIH S10OD021785) in the in vivo study.

Funding

This work was supported by NIH Grant AR073233 awarded to W.A. The study was also partly supported by award number P30CA014089 from the National Cancer Institute.

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  1. Department of Cancer Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Yonghwan Shin, Sungmin Kim, Suhn K. Rhie & Woojin An

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  1. Yonghwan Shin
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  2. Sungmin Kim
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Contributions

YS and WA conceived and designed the study. YS and SK performed experiments with contributions of SR. YS, SK, and WA analyzed data. YS, SK, and WA wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Woojin An.

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All animal experiments were approved by the Institutional Animal Care and Use Committee of University of Southern California (NO. 11673), and were conducted in accordance with the committee’s institutional guidelines.

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Shin, Y., Kim, S., Rhie, S.K. et al. HDAC1 has intrinsic protease activity and regulates transcription through clipping histone H3 N-terminal tail. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01622-4

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