Understanding HAT1: A Comprehensive Review of Noncanonical Roles and Connection with Disease

Abstract

Histone acetylation plays a vital role in organizing chromatin, regulating gene expression and controlling the cell cycle. The first histone acetyltransferase to be identified was histone acetyltransferase 1 (HAT1), but it remains one of the least understood acetyltransferases. HAT1 catalyzes the acetylation of newly synthesized H4 and, to a lesser extent, H2A in the cytoplasm. However, 20 min after assembly, histones lose acetylation marks. Moreover, new noncanonical functions have been described for HAT1, revealing its complexity and complicating the understanding of its functions. Recently discovered roles include facilitating the translocation of the H3H4 dimer into the nucleus, increasing the stability of the DNA replication fork, replication-coupled chromatin assembly, coordination of histone production, DNA damage repair, telomeric silencing, epigenetic regulation of nuclear lamina-associated heterochromatin, regulation of the NF-κB response, succinyl transferase activity and mitochondrial protein acetylation. In addition, the functions and expression levels of HAT1 have been linked to many diseases, such as many types of cancer, viral infections (hepatitis B virus, human immunodeficiency virus and viperin synthesis) and inflammatory diseases (chronic obstructive pulmonary disease, atherosclerosis and ischemic stroke). The collective data reveal that HAT1 is a promising therapeutic target, and novel therapeutic approaches, such as RNA interference and the use of aptamers, bisubstrate inhibitors and small-molecule inhibitors, are being evaluated at the preclinical level.

Prognostic Value of Histone Acetyl Transferase 1 (HAT-1) and Inflammatory Signatures in Pancreatic Cancer

“…Indeed, past works have shown a direct relationship between the protein expression of PGAM1 and reduced survival in PDAC patients [40,41]. HAT1 seems to present an important succinyl transferase activity in histones and non-histone proteins like PGAM1 [29]. The succinylation of PGAM1 by HAT1 seems to play a critical role in promoting tumor progression in vitro and in vivo in various types of cancer, including PDAC [42].…”

“…HAT-1 is a molecule mainly implicated in the enzymatic acetylation of K5 and K12 in the N-terminus of H4 in a newly assembled H3/H4 dimer in the cytoplasm [28]. However, HAT-1 also fulfills a wide range of non-canonical actions, including translocation of H3H4 into the nucleus; regulation of H4 gene expression; DNA replication fork stability and replication-coupled chromatin assembly; DNA damage repair and telomeric silencing; epigenetic regulation of nuclear lamina-associated heterochromatin; and promoting acetylation and succinylation processes [29]. HAT-1 first interacts and forms a complex with RBBP7, leading to the acetylation of the H3/H4 heterodimer as previously mentioned.…”

“…Finally, immunohistochemical analysis shows that IL-10 is expressed in 6 pancreatic cancer patients, whereas 31.7% present negative expression for this cy The median survival for patients with pancreatic cancer and negative tissue expre IL-10 was 4 (4-7) months. However, in the case of patients with low-medium exp it was 11 (7)(8)(9)(10)(11)(12)(13)(14)(15)(16) months, increasing to 24 (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) months in patients with a high exp (Figure 2B). Global comparisons showed that the significance value was p < 0.001 * a hazard ratio of 0.265 and a 95% confidence interval [0.142-0.500] in patients w expressions of IL-10.…”