Histone modification is important for maintaining chromatin structure and function. Recently, histone acetylation has been shown to have a critical regulatory role in both transcription and DNA repair. We report here that expression of histone acetyltransferase (HAT) genes is associated with cisplatin resistance. We found that Tip60 is overexpressed in cisplatin-resistant cells. The expression of two other HAT genes, HAT1 and MYST1, did not differ between drug-sensitive and -resistant cells. Knockdown of Tip60 expression rendered cells sensitive to cisplatin but not to oxaliplatin, vincristine, and etoposide. Tip60 expression is significantly correlated with cisplatin sensitivity in human lung cancer cell lines. Interestingly, the promoter region of the Tip60 gene contains several E boxes, and its expression was regulated by the E-box binding circadian transcription factor Clock but not by other E-box binding transcription factors such as c-Myc, Twist, and USF1. Hyperacetylation of H3K14 and H4K16 was found in cisplatin-resistant cells. The microarray study reveals that several genes for DNA repair are down-regulated by the knockdown of Tip60 expression. Our data show that HAT gene expression is required for cisplatin resistance and suggest that Clock and Tip60 regulate not only transcription, but also DNA repair, through periodic histone acetylation.Our research has focused on factors affecting cellular sensitivity of solid tumors to anticancer agents and investigation of promising molecular targets for cancer treatment (1, 2). Among many drugs, cis-diamminechloroplatinum (II) (cisplatin) plays a crucial role in the treatment of various solid tumors (3, 4). Cisplatin has been shown to form a cross-link between adjacent purines in genomic DNA and can cause DNA-damaging signals to induce apoptosis (1, 2). Cisplatin treatment also induces oxidative and endoplasmic reticulum stresses (5). Thus, the nature of cellular sensitivity to cisplatin is highly complex.The development of cisplatin resistance is a major clinical limitation in cancer chemotherapy. Cisplatin resistance is influenced by many factors which affect intracellular drug accumulation (6 -8), increased activity of intracellular thiol production (9, 10), and DNA repair (11, 12). However, little is known about the molecular mechanisms involved in drug resistance. Cellular factors involved in transcription contribute to the induction of apoptosis or transient or acquired resistance. We have tried to identify the cisplatin-inducible transcription factors and transcription-related factors that are highly expressed in drug-resistant cells (1, 2, 13). We have previously shown that expression of activating transcription factor 4 (ATF4) 2 is inducible by cisplatin treatment and is high in cisplatin-resistant cells (14). The cellular level of ATF4 expression correlates with cisplatin sensitivity in human lung cancer cell lines. DNA microarray analysis has revealed that ATF4 regulates genes involved in glutathione biosynthesis and conjugation (15). Interestingly, ...

A remarkable rise in intraocular pressure occurs during hemodialysis in eyes with an impaired aqueous outflow, when serum osmolality decreases rapidly.

Quercetin upregulates the antioxidant peroxiredoxins through the activation of the Nrf2/NRF1 transcription pathway and protects against oxidative stress-induced ocular disease.

No abstract

NCT can be more affected by CCT than GAT. CCR could influence the measurements of GAT, but not those by NCT. CCT and CCR can therefore influence the discordance of IOP readings taken with NCT and GAT.