Many aspects of genome regulation and metabolism require histone acetylation. Accordingly, dysfunctional histone acetylation has been implicated in numerous diseases, including cancer. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate acetylation of histones and non-histone. HATs catalyze the acetylation of core histones through the addition of an acetyl group to the lysine residue on the terminal tail of the histones. HDAC enzymes can remove these acetyl groups, leading to the formation of a condensed and more transcriptionally silenced chromatin. HATs have three main groups and the largest and most diverse (MYST family) includes MOZ, YBF2, MOF, and Tip60. Tip60 functions in signaling, apoptosis, DNA damage repair, cell cycle progression, and transcriptional regulation. Tip60 is critical for the induction of the DNA damage response. Here, TH1834 is a specific Tip60 HAT inhibitor. It induces apoptosis and increases DNA damage in breast cancer.

TH1834 treatment significantly reduces the viability of MCF7 cells. It highly significantly increases cytotoxicity in MCF7 cells. In addition, TH1834 induces caspase 3 activations in MCF7 cells. TH1834 also significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage in breast cancer. Furthermore, the combination of ionizing radiation (IR) and TH1834 treatment of the prostate cancer (DU-145) cell line also induces the appearance of a sub-G1 peak indicating cell death.

TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage in breast cancer. It did not affect the activity of related HAT MOF. TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer.