Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease

Abstract

The lysine acetyltransferase 6 (KAT6) histone acetyltransferase (HAT) complexes are highly conserved from yeast to higher organisms. They acetylate histone H3 and other nonhistone substrates and are involved in cell cycle regulation and stem cell maintenance. In addition, the human KAT6 HATs are recurrently mutated in leukemia and solid tumors. Therefore, it is important to understand the mechanisms underlying the regulation of KAT6 HATs and their roles in cell cycle progression. In this minireview, we summarize the identification and analysis of the KAT6 complexes and discuss the regulatory mechanisms governing their enzymatic activities and substrate specificities. We further focus on the roles of KAT6 HATs in regulating cell proliferation and stem cell maintenance and review recent insights that aid in understanding their involvement in human diseases.

Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding

“…KAT6A can acetylate nonhistone and histone substrates in mammals, and functions as a positive or negative regulator (16). KAT6A interacts with transcriptional factors, such as p53 and RUNX1, to activate gene transcriptions by acetylating histones near target gene promoters (15, 40).…”

“…Dysregulation of the KAT6A histone acetyltransferase activity or aberrant expression of KAT6A has been associated with oncogenesis in leukemia (10-13) and breast cancer (14). KAT6A's oncogenic activity was first identified as a recurrent fusion partner of the CREB binding protein (CBP) as a consequence of gene translocation, t(8;16)(p11;p13) in the FAB M4/M5 subtype of acute myeloid leukemia (AML) (13). Then, the KAT6A-TIF2 fusion was identified as a consequence of another translocation, inv(8)(p11;p13) in AML.…”

“…In addition, KAT6A and the related factor Lysine acetyltransferase 6B (KAT6B, also known as MORF) form a tetrameric complex with ING5 (Inhibitor of growth 5), EAF6 (Esa1-associated factor 6 ortholog), and the bromodomain-PHD finger protein BRPF1 (15). Increasing evidence suggests that KAT6A is implicated in regulating tumor progression (16), but mechanisms that facilitate its oncogenic activity independent of gene fusion remain elusive.…”

Recognition of Histone H3K14 Acylation by MORF

“…The MORF KAT complex is required for neurogenesis and transcriptional regulation, and its genomic translocations and mutations are associated with cancer and developmental diseases (Huan et al, 2016; Yang, 2015). In addition to the catalytic MORF subunit, the native MORF complex contains the adaptor proteins BRPF1, ING5 and MEAF6 (Feng et al, 2016).…”

Limiting PCNA-unloading at the G1/S transition

“…4 The Drosophila KAT6, Enok, was found to play critical roles in neuroblast proliferation, 5 but information regarding the underlying mechanisms has been long lacking. In our recently published study, we sought to investigate how Enok regulates cell cycle progression by identifying its novel interacting partners.…”