HDAC8

HDAC8 (histone deacetylase 8) is a zinc-dependent class I histone deacetylase that regulates chromatin organization and transcription through deacetylation of both histone and nonhistone substrates, placing it at the center of epigenetic control mechanisms.^[1] Mechanistically, HDAC8 participates in transcriptional regulation, cell-cycle progression, and genome maintenance, and recent evidence shows that HDAC8 activity contributes to replication-fork stability through regulation of the cohesin component SMC3 and suppression of replication-associated stress.^[2] These functions connect HDAC8 to biological processes that govern proliferation, differentiation, and cellular homeostasis.^[1][2] In disease settings, dysregulated HDAC8 has been implicated in multiple cancers, where it is associated with tumor cell proliferation, metastasis, immune evasion, and drug resistance, supporting its relevance as an epigenetic therapeutic target.^[3][1] HDAC8 has also been linked to developmental and genetic disorders, including Cornelia de Lange syndrome and X-linked intellectual disability, indicating functions that extend beyond oncology.^[1] Compared with related class I isoforms such as HDAC1, HDAC2, and HDAC3, HDAC8 displays distinct structural and substrate-recognition properties, recognizes both histone and nonhistone proteins, and therefore offers opportunities for isoform-selective pharmacological modulation.^[1][4] For experimental applications, selective HDAC8 inhibitors have been developed to minimize the off-target effects associated with pan-HDAC inhibition, and these compounds are widely used to investigate HDAC8-dependent pathways and evaluate therapeutic strategies in cancer and other disease models.^[1][4]