KAT8, also known as lysine acetyltransferase 8 or MOF (Male absent on the first), is a key enzyme in epigenetic regulation, primarily recognized for its histone acetyltransferase activity. It modulates chromatin structure by acetylating histone H4 lysine 16 (H4K16), which impacts diverse cellular processes such as gene expression, cell proliferation, differentiation, and apoptosis. KAT8 is part of multiprotein complexes like the male-specific lethal (MSL) and non-specific lethal (NSL) complexes, regulating a wide range of transcriptional activities [3].

In colorectal cancer, deletion of KAT8 inhibited tumor growth, especially in a high-lactic tumor microenvironment. KAT8 acts as a pan-lysine lactylation (Kla) writer, and its catalyzed lactylation of eEF1A2 at K408 boosts translation elongation and protein synthesis, contributing to tumorigenesis [1]. In bladder cancer, suppression of KAT8-mediated acetylation of YEATS4 with the inhibitor MG149 decreased YEATS4 acetylation, reduced cell viability, and sensitized cells to cisplatin treatment [4]. In trophoblasts, trophoblast-specific deletion of Kat8 led to extraembryonic ectoderm abnormalities and embryonic lethality, as KAT8 regulates the transcriptional activation of the trophoblast stemness marker CDX2 via acetylating H4K16 [2].

In conclusion, KAT8 plays essential roles in multiple biological processes through its epigenetic regulatory functions. Model-based research, especially using gene knockout (KO) or conditional knockout (CKO) mouse models, has revealed its significance in diseases such as colorectal cancer, bladder cancer, and early pregnancy-related disorders. Understanding KAT8's functions provides potential therapeutic targets for these diseases.

References:

1. Xie, Bingteng, Zhang, Mengdi, Li, Jie, Li, Mo, Pu, Yang. 2024. KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2314128121. doi:10.1073/pnas.2314128121. https://pubmed.ncbi.nlm.nih.gov/38359291/

2. Bi, Shilei, Huang, Lijun, Chen, Yongjie, Wang, Fengchao, Zhang, Shuang. 2024. KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2. In Nature communications, 15, 5602. doi:10.1038/s41467-024-49930-6. https://pubmed.ncbi.nlm.nih.gov/38961108/

3. Yoo, Lindsey, Mendoza, David, Richard, Allison J, Stephens, Jacqueline M. 2024. KAT8 beyond Acetylation: A Survey of Its Epigenetic Regulation, Genetic Variability, and Implications for Human Health. In Genes, 15, . doi:10.3390/genes15050639. https://pubmed.ncbi.nlm.nih.gov/38790268/

4. Xie, Miner, Zhou, Liwen, Li, Ting, Kang, Tiebang, Wu, Yuanzhong. 2024. Targeting the KAT8/YEATS4 Axis Represses Tumor Growth and Increases Cisplatin Sensitivity in Bladder Cancer. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2310146. doi:10.1002/advs.202310146. https://pubmed.ncbi.nlm.nih.gov/38526153/