Exploring the in vitro and in vivo effects of Tip60 inhibition following TH1834 treatment

The acetyltransferase Tip60 plays critical roles in multiple critical cellular pathways through its functions as an epigenetic and transcriptional regulator, and as a master regulator of the DNA double-strand break response. In cancer, Tip60 is frequently downregulated and mislocalised, contributing to tumour progression at least partly through altered gene expression patterns. Recent evidence also suggests Tip60 has a role in neurological disorders, particularly in processes related to features such as the neurodegeneration seen in Alzheimer’s disease. While some roles for Tip60 have been defined, many roles have been difficult to explore due to its essential role in cell survival, with current approaches including knockouts/siRNA, inducing apoptosis and significantly complicating any analysis of Tip60-regulated activity and signalling.Here we evaluated the efficacy of TH1834, a novel dual-action Tip60 inhibitor targeting both epigenetic regulation and the DNA damage response pathway. TH1834 drug assays against multiple breast cancer subtypes, and in combination with other inhibitors demonstrated significant anti-tumour specificity of TH1834 and its potential synergies with current chemotherapeutics, particularly against aggressive breast cancer subtypes. This approach highlights the potential of targeting epigenetic mechanisms for cancer therapy, which is significant as epigenetic modifications are reversible.Next generation sequencing analysis revealed TH1834-induced transcriptomic changes in clinically relevant breast cancer subtypes, providing insights into unique subtype-specific roles of Tip60. These findings contribute to the growing understanding of precision medicine approaches in breast cancer treatment, emphasizing the importance of molecular profiling for informing chemotherapeutic decisions.Furthermore, our investigation of Tip60's role extends beyond cancer, to its important new role in neurological disorders. We are the first to explore the effects of Tip60 inhibition in neurological tissue in vivo, investigating in vivo effects of TH1834 treatment on the brain, supporting investigations into Tip60’s role in neurodegenerative disorders, and its potential role as a biomarker and therapeutic target.This comprehensive analysis of Tip60's diverse functions both in vivo and in vitro provides valuable insights for both cancer treatment (using TH1834 therapeutically), and foundationally defining TH1834 effects in vivo in neurological tissue.<br>