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

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272621 | GEO | 2025/12/23

REPOSITORIES: GEO

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Project description:Hypoxia in stem cell niches and inner core of solid tumors contributes to cellular senescence and differentiation inhibition. It directly increases histone methylationby inhibiting the activities of O2-and α-ketoglutarate (α-KG)-dependent histone lysine demethylases. This study is the first to demonstrate how the hypoxic increment of methylated histones cross-talks with other epigenetic changes, such as histone clipping and heterochromatin redistribution, named senescence-associated heterochromatin foci (SAHF), which are found during oncogene-induced senescence (OIS). This study showed that Raf activation in primary human fibroblasts IMR90 increases mature cathepsin L (CTSL)-mediated cleavage of H3, H2B, and H4. Hypoxia prevented H3 cleavage not by inhibiting CTSL but by increasing H3K18me3 and H3K23me3 nearby cleaved site of H3. Forced expression of cleaved H3 in IMR90 cells induced senescence even under hypoxia, suggesting that hypoxia breaks this positive feedback senescence driving circle by increasing methylated histones. The decrease in methylated histones is necessary for OIS to trigger histone clipping and SAHFs, but hypoxia maintains methylated histones to prevent both. Forced reduction of methylated histones in hypoxic cells using inhibitors of methyl-transferases makes hypoxic conditions unable to prevent OIS from inducing both histone clipping and SAHFs. Reversely forced enhancement of methylated histones in normoxic cells using inhibitors of histone demethylases protected histones from clipping during OIS but failed to block SAHFs. Altogether, the maintenance of methylated histones, especially H3K23me3 and H3K18me3, is sufficient to protect histones from clipping during OIS, but not for inhibiting SAHFs, suggesting that besides inhibiting KDMs, hypoxia adopts other methods to inhibit SAHFs. These findings provide a novel mechanism by which hypoxia affects cell fate by increasing methylated histones that protect histones and chromatin from dramatic epigenetic changes.

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

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