HAT1 (Histone Acetyltransferase 1)

HAT1 drives LGG malignancy by remodeling the immune microenvironment and activating key oncogenic pathways. Its spatial enrichment in malignant niches and druggability provide a novel basis for targeted-immunotherapy combinations.

Correspondingly, targeted inhibition of RPA1 lactylation at K88, using a competitive peptide, reverses radioresistance in GBM cells. Collectively, these findings establish the lactate-driven HAT1-RPA1 lactylation axis as a critical regulator of radioresistance and nominate both HAT1 and lactylated RPA1 as novel therapeutic targets in GBM.

TCE significantly altered the expression of approximately 25% of miRNAs related to cancer pathway in the miRNA array panel, as it upregulated 19 miRNAs and downregulated 4 miRNAs of the tested 84 miRNAs. Considering the effects on chromatin modification, proliferation rate, and miRNAs, it can be concluded that these mechanisms may be involved in TCE-induced nephrotoxicity.

These findings suggest that the CREB3L2/HAT1/SREBP1 regulatory axis drives lenvatinib resistance and HCC progression by impacting lipid metabolism. Targeting CREB3L2 alongside lenvatinib improves the efficacy of treating HCC.

Interestingly, we also found that K15 auto-lactylation of HAT1 can modulate its lactyltransferase activity. In conclusion, our research reveals that HAT1-regulated RPA1 lactylation plays an important role in homologous recombination and radioresistance, suggesting that HAT1 may become a potential therapeutic target for reversing the radioresistance caused by lactate accumulation in cancer cells.

In conclusion, succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer. Our finding provides new insights into the mechanism by which post-translational modifications (PTMs) confer the conversion of tumor suppressor function to oncogene.

In addition, the inhibition of HAT1 promoted cell cycle arrest, and reduced cyclin-dependent kinase (CDK)2, CDK4 and cyclin E levels in OC cells. Taken together, the present data suggested that HAT1 served an oncogenic role in OC; therefore, HAT1 may represents a new potential therapeutic target in OC treatment.

Pharmacological disruption using 4-Deoxyuricine (AID antagonist) and MG149 (HAT1 inhibitor) reduces JAG1 acetylation, attenuates NOTCH signaling, and reshapes the TME by depleting AID/HAT1-JAG1 axis and enhancing the infiltration of T cells, NK cells, and B cells...These results resolve the paradox of NOTCH inhibitor resistance by identifying JAG1's epigenetic priming as a prerequisite for ligand-receptor signaling. Targeting the AID/HAT1-JAG1 axis offers a dual therapeutic strategy to overcome TME-mediated therapy resistance and provides a blueprint for precision immunotherapy in AID-positive TNBC subgroups.

The lower part of the figure highlights that succinylation promotes tumor cell hypoxic adaptation and immune escape by stabilizing HIF-1α, inducing ROS production, and SDH dysfunction. TCA, Tricarboxylic acid cycle PDH, Pyruvate dehydrogenase SDH, Succinate dehydrogenase GLUD1, Glutamate dehydrogenase 1 HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2 FEN1, Flap endonuclease 1, SIRT, Sirtuin family proteins, KAT2A, Lysine acetyltransferase 2A alpha-KGDH, Alpha-ketoglutarate dehydrogenase CPT1A, Carnitine palmitoyltransferase 1A HAT1, Histone acetyltransferase 1 HIF-1α, Hypoxia-inducible factor 1 alpha ROS Reactive oxygen species.This figure was created by Biorender.com.(https://BioRender.com).

ECGG blocked the migration of MTS cells into Matrigel and decreased the expression of matrix metalloproteinase MMP2. These results suggest that EGCG could prevent cell migration from small nonirrigated tumors in vitro by affecting cell adhesion molecules such as MMP2, decreasing the catalytic activity of enzymes associated with metastasis.

miRNA array analysis showed notable and significant reductions in the expression levels of several miRNAs. The results obtained from this comprehensive study are expected to make a significant contribution to the elucidation of ZEA toxicity.