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

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.