| KAT8, also known as MOF or MYST1, is an evolutionarily conserved lysine acetyltransferase of the MYST family that serves as the major histone H4 acetyltransferase at lysine 16 and, in specific contexts, at lysines 5 and 8, thereby modulating chromatin compaction, transcriptional initiation and broader nuclear programs. The protein contains the characteristic MYST acetyltransferase core with a C2HC zinc finger and an acetyl-CoA–binding motif, and functions as the catalytic subunit within two distinct multiprotein assemblies: the MSL complex, which mediates the bulk of H4K16ac to prevent higher-order chromatin folding and to support X‑chromosome dosage compensation, and the NSL complex, which targets H4K5ac and H4K8ac at promoters to promote RNA polymerase II recruitment and transcription initiation. Through these complexes, KAT8 installs H4K16ac across genic bodies and regulatory regions, maintaining open chromatin and influencing expression of genes involved in cell proliferation, differentiation, apoptosis and stem cell identity, while NSL-mediated KAT8 activity at transcription start sites integrates with core transcriptional and signaling networks required for normal development and cellular homeostasis. Beyond histones, KAT8 acetylates non-histone substrates including TP53, LMNA, COX17 and ALKBH5, extending its influence to mitochondrial gene expression, DNA damage responses, nuclear architecture and RNA metabolism and highlighting acetylation-dependent control of cellular stress and survival pathways. In glioblastoma, MYST1/KAT8 contributes to tumor progression by activating EGFR signaling: KAT8 is upregulated in GBM, supports EGFR expression and downstream pathway activation, and its knockdown suppresses proliferation, migration and tumor growth, implicating H4K16ac-driven transcriptional programs in EGFR-dependent oncogenic signaling. In esophageal squamous cell carcinoma, MOF/KAT8 is highly expressed in tumors, correlates with poor prognosis, and its acetyltransferase activity is required for oncogenic effects; USP10 stabilizes MOF by deubiquitinating Lys410, promoting H4K16ac enrichment at the ANXA2 promoter, increasing ANXA2 transcription via JUN, and thereby activating Wnt/β‑catenin signaling to drive proliferation and metastasis, defining a USP10–MOF–ANXA2 axis in ESCC. Genetic studies in humans link KAT8 variants and deficient H4K16 acylation to syndromic intellectual disability, epilepsy, autism and cerebral developmental anomalies, and KAT8 is required for cerebral and neural stem/progenitor development, placing its chromatin-modifying activity at the heart of neurodevelopmental gene expression programs. KAT8 also participates in mitochondrial transcription control by associating with mitochondrial DNA and acetyltransferase‑dependently regulating respiratory gene expression and influencing autophagy outcomes via H4K16ac dynamics, connecting its chromatin function to metabolic and stress responses. |
