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kat6a

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Official Full Name
K(lysine) acetyltransferase 6A
Background
MYST histone acetyltransferase (monocytic leukemia) 3, also known as MYST3, is an enzyme that, in humans, is encoded by the MYST3 gene.
Synonyms
KAT6A; K(lysine) acetyltransferase 6A; RUNXBP2; MOZ; Monocytic leukemia zinc finger protein; ZNF220; MOZ, YBF2/SAS3, SAS2 and TIP60 protein 3; EC 2.3.1.48; runt-related transcription factor binding protein 2; MGC167033; Runt-related transcription factor-binding protein 2; Zinc finger protein 220; EC 3.1.26.4; MYST3; histone acetyltransferase MYST3; MYST-3; OTTHUMP00000197392; OTTHUMP00000197394; OTTHUMP00000225722; MYST histone acetyltransferase (monocytic leukemia) 3; bmd; histone acetyltransferase KAT6A

Recent Research

The monocytic leukemia zinc finger gene (MOZ/KAT6A/MYST3) was first identified in a recurrent chromosomal translocation (t8; 16) (p11; p13) associated with acute myeloid leukemia, where it is fused to the CREB binding protein. KAT6A-related translocations are associated with the same type of acute myeloid leukemia (AML), with blast cells of a monocytoid phenotype having pronounced erythrophagocytic activity. KAT6A is essential for the self-renewal of hematopoietic stem cells, and KAT6A fusion proteins enable the transformation of non-self-renewing myeloid progenitors into leukemia stem cells. It has been shown that KAT6A cooperates with MLL to regulate HOX gene expression in human cord blood CD341 cells.

KAT6A has been implicated in both the promotion and inhibition of senescence. Some studies have shown the role of KAT6A in cellular senescence, KAT6A is a potent inhibitor of senescence via the INK4A-ARF pathway. Primary mouse embryonic fibroblasts (MEFs) isolated from KAT6A-deficient embryos exhibit premature senescence. Moreover, genes over-expressed in aggressive and highly proliferative cancers are expressed at low levels in KAT6A-deficient MEFs. It has been shown that KAT6A is required to maintain normal levels of histone 3 lysine 9 (H3K9) and H3K27 acetylation at the transcription start sites of at least four genes, Cdc6, Ezh2, E2f2 and Melk, and normal mRNA levels of these genes.

The chromosome 8p11-p12 amplicon is present in 12% to 15% of breast cancers, resulting in an increase in copy number and expression of several chromatin modifiers in these tumors, including KAT6A. Some studies showed the amplification and over-expression of KAT6A in SUM-52 breast cancer cells. It has identified KAT6A as a potential driving oncogene. Knockdown of KAT6A in SUM-52 cells, a luminal breast cancer cell line harboring the amplicon, resulted in reduced growth rate compared to non-silencing controls and profound loss of clonogenic capacity both in mono-layer and in soft agar. The normal cell line MCF10A did not exhibit slower growth with knockdown of KAT6A. SUM-52 cells with KAT6A knockdown formed fewer mammospheres in culture compared to controls, suggesting a possible role for KAT6A in self-renewal.

In addition, KAT6A is indispensable, especially, for the development of single hematopoietic stem cell (HSC), but is less important for the differentiation of progenitors. Hematopoietic progenitors develop in the absence of KAT6A early in development, albeit in reduced numbers, and these are able to form all mature blood cell types. In particular, KAT6A null fetuses have a normal hematocrit, although there is a delay in erythrocyte maturation. KAT6A is a lysine acetyltransferase required for H3K9 acetylation at target loci, in particular at Hox loci. KAT6A is a global activator of Hox gene expression and the absence of KAT6A results in homeotic transformation of body segment identity. The function of KAT6A resembles that of the chromatin activator and trithorax group protein MLL1 (KTM2A). KAT6A cooperates with MLL1 to regulate gene expression both during embryogenesis and in the hematopoietic system.BMI1 directly opposes the function of KAT6A in Hox gene regulation during embryonic development. It has been shown that deletion of KAT6A leads to a rapid loss of adult bone marrow HSCs.

References:

  1. Sheikh B N, et al. KAT6A (MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway. Oncogene, 2015, 34(47):5807-5820.
  2. Chinen Y, et al. The leucine twenty homeobox (LEUTX) gene, which lacks a histone acetyltransferase domain, is fused to KAT6A in therapy-related acute myeloid leukemia with t(8;19)(p11;q13). Genes Chromosomes & Cancer, 2014, 53(4):299-308.
  3. Turner-Ivey B, et al. KAT6A, a chromatin modifier from the 8p11-p12 amplicon is a candidate oncogene in luminal breast cancer. Neoplasia, 2014, 16(8):644-655.
  4. Sheikh B N, et al. KAT6A (KAT6A) is essential for the maintenance of classically defined adult hematopoietic stem cells. Blood, 2016, 128(19):2307-2318.