KAT8/MOF-Mediated Anti-Cancer Mechanism of Gemcitabine in Human Bladder Cancer Cells

Abstract

Histone acetylation is a well-characterized epigenetic modification controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalanced histone acetylation has been observed in many primary cancers. Therefore, efforts have been made to find drugs or small molecules such as HDAC inhibitors that can revert acetylation levels to normal in cancer cells. We observed dose-dependent reduction in the endogenous and exogenous protein expression levels of KAT8 (also known as human MOF), a member of the MYST family of HATs, and its corresponding histone acetylation at H4K5, H4K8, and H4K16 in chemotherapy drug gemcitabine (GEM)-exposed T24 bladder cancer (BLCA) cells. Interestingly, the reduction in MOF and histone H4 acetylation was inversely proportional to GEM-induced γH2AX, an indicator of chemotherapy drug effectiveness. Furthermore, pGL4-MOF-Luc reporter activities were significantly inhibited by GEM, thereby suggesting that GEM utilizes an MOF-mediated anti-BLCA mechanism of action. In the CCK-8, wound healing assays and Transwell ® experiments, the additive effects on cell proliferation and migration were observed in the presence of exogenous MOF and GEM. In addition, the promoted cell sensitivity to GEM by exogenous MOF in BLCA cells was confirmed using an Annexin V-FITC/PI assay. Taken together, our results provide the theoretical basis for elucidating the anti-BLCA mechanism of GEM.

KAT8 acetylation-controlled lipolysis affects the invasive and migratory potential of colorectal cancer cells

“…KAT8 depletion was shown to promote migration and invasion of tumor cells recently [ 44 ]. Here, we assessed the effect of KAT8 acetylation on CRC progression.…”

KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy

“…Interestingly, KAT8 was identified as one of the risk candidate genes for AD 2 . KAT8 inhibition may also have selective toxicity and antiproliferative activity against cancer cells 11 , 49 and potentially normalise myocardial functions in the context of cardiovascular diseases and ischemia–reperfusion injury 47 . By looking at MG149 in the context of mitophagy, we have underlined a new area in which modulating KAT8 inhibition may be of use in the study of PD.…”

KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy

“…Interestingly, KAT8 was identified as one of the risk candidate genes for AD (Bellenguez, C., et al ., 2022). KAT8 inhibition may also have selective toxicity and antiproliferative activity against cancer cells (Zhu, H., et al ., 2021), (Fiorentino, F., et al ., 2023) and potentially normalise myocardial functions in the context of cardiovascular diseases and ischemia-reperfusion injury (Yu, L., et al ., 2018). By looking at MG149 in the context of mitophagy, we have underlined a new area in which modulating KAT8 inhibition may be of use in the study of PD.…”