The epigenetic writer’s histone acetyltransferases (HATs) are responsible for promoting the accessibility of genes and genomic regions by histone acetylation and subsequent euchromatin formation. Some HATs display additional succinyl-transferase abilities and provide secondary regulatory mechanisms [
94‐
97]. HATs can be grouped into the families of GNATs, MYST, as well as p300/CBP [
98]. The most prominent HAT, E1A binding protein p300, has been well described due to its involvement in the regulation of global transcriptional regulation and its potential to target all histone subunits [
99]. In pancreatic cancer, both tumor-promoting and tumor-suppressing functions have been described for p300. The occurrence of the
EP300 gene mutation in pancreatic cancer (Fig.
2b) is a hint towards its tumor-suppressive function. On the other hand, multiple studies described an increased activity of the proto-oncogene MYC mediated by p300 in other tumor entities [
100,
101]. In a recent study, it was found that mutations in
EP300 lead to resistance against inhibitors of porcupine (PORCN), an endoplasmic reticulum O-acyltransferase, in RNF43-mutant pancreatic cancers [
102]. PORCN is responsible for the palmitoylation of Wnts, which is necessary for their secretion and activation of the receptors [
103,
104]. Approximately 5–10% of PDAC cases contain mutations in the RNF43 E3 ubiquitin ligase [
6,
105], which can direct Wnt surface receptors to the proteasome [
106,
107]. Therefore, PDACs with inactivated RNF43 express a higher level of Wnt receptors, such as Frizzleds (FZDs) and LRP5/6, making them more susceptible to inhibitors targeting ligand-activated Wnt signaling [
108]. p300 plays a crucial role in the expression of GATA6, and the inactivation of
EP300 leads to dedifferentiation and a shift towards a more basal-like subtype. This dedifferentiation process, which bypasses WNT-dependent pathways, explains the resistance of
RNF43/
EP300 double mutant PDACs to PORCN inhibitors [
102].
Furthermore, elevated levels of miRNAs that target p300 and subsequent low expression of p300 were observed in PDAC cell lines displaying high metastatic potential in orthotropic mouse models [
109]. Irrespective of metastatic potential, multiple studies have shown that inhibition of p300 and its coactivator CBP also improved gemcitabine sensitivity and reduced cell-cycle progression and proliferation in PDAC cells [
110‐
113]. Shi et al. elaborated on this topic and observed a correlation between platelet-derived growth factor C (PDGFC) expression and gemcitabine resistance as a result of platelet-derived growth factor receptor alpha (PDGFRα) and beta (PDGFRβ) activation. They showed that p300 binds to the promoter site of the
PDGFC gene, and inhibition of p300 reduced PDGFC expression [
113]. Since PDGFRβ signaling has been linked to a more aggressive and metastatic phenotype in PDAC [
114,
115], the observed regulation of PDGFC by p300 provides evidence for a more aggressive phenotype orchestrated by p300-dependent chromatin remodeling [
113]. In a recent study, promising findings in mice regarding a novel dual inhibitor, XP-524, targeting BET proteins and p300 were presented. The results demonstrated improved survival and a reorganized microenvironment upon XP-524 treatment, resulting in enhanced immune infiltration [
116]. Furthermore, the researchers noted that the inclusion of an anti-PD-1 antibody in the treatment regimen further enhanced survival. These findings suggest the potential of XP-524 as a therapeutic approach, possibly in combination with immune checkpoint inhibitors, for improved outcomes in the future [
116]. Regarding other HATs, researchers discovered an increased expression of histone acetyltransferase 1 (HAT1) in pancreatic tumor tissue compared to healthy tissue, and high expression of HAT1 correlated with a worse prognosis [
117]. The knockdown of
HAT1 resulted in reduced proliferation and tumor volume in the investigated human cell lines and murine models. The researchers additionally observed a correlation between HAT1 and PD-L1 expression and identified increased recruitment of BRD4 to the PD-L1 promoter in a HAT1-dependent manner. Whether HAT1 mediates BRD4 recruitment via H4K5 acetylation or its newly discovered succinyl-transferase activity remains unclear [
94,
117]. Regardless, the results indicate that HAT1 might contribute to immune evasion during PDAC progression. Similar to HAT1, lysine acetyltransferase 2A (KAT2A/GCN5) also showed increased, aberrant expression in PDAC tissue and significantly worse overall survival in the KAT2A
high group in a cohort of 40 patients [
97]. KAT2A knockdown resulted in reduced proliferation, impaired wound healing, and decreased invasion ability. Mechanistically, KAT2A was found to transcriptionally regulate YWHAZ (also known as 14-3-3ζ) through H3K79 succinylation [
97]. 14-3-3ζ stabilizes β-catenin and maintains canonical Wnt signaling [
118]. The knockdown of KAT2A led to reduced expression of 14-3-3ζ and subsequent degradation of β-catenin [
97]. This, in turn, resulted in decreased expression of β-catenin target genes, including c-MYC, GLUT1, LDHA, and cyclin D1. Interestingly, the researchers attempted to restore the phenotype of KAT2A knockdown cells by reintroducing KAT2A
wt. They observed successful reversion of the phenotype; however, when they reconstituted a succinyl-transferase defective form of KAT2A (KAT2A
Y645A), they failed to restore the expression of 14-3-3ζ and H3K79 succinylation, despite the rescue of the H3K9 acetylation. These results emphasize the significance of acetylation-independent functions of KAT2A, particularly concerning the aggressiveness of PDAC [
97].