Tip60 Is Regulated by Circadian Transcription Factor Clock and Is Involved in Cisplatin Resistance

Abstract

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, ...

Histone modifications in DNA damage response

“…Besides chromatin relaxation, Tip60-mediated acetylation of phospho-H2Av, H2AX homolog in Drosophila melanogaster, induces the exchange of phospho-H2Av with unmodified H2Av (Kusch et al, 2004), while Tip60-dependent H4K16 acetylation diminishes 53BP1 binding to H4K20me2 and promotes HR repair (Tang et al, 2013). Tip60 depletion impairs homologous recombination and rendered cells sensitive to cisplatin (House et al, 2014;Miyamoto et al, 2008;Tang et al, 2013). Furthermore, similar to human CBP/p300 or yeast Rtt109, histone acetyltransferase 1 in yeast and human cells is also required for the incorporation of acetylated H3 at sites of double-strand breaks, and facilitates subsequent recruitment of RAD51 to promote efficient homologous recombination (Qin and Parthun, 2002;Yang et al, 2013).…”

Enhanced Expression of PCAF Endows Apoptosis Resistance in Cisplatin-Resistant Cells

“…We have previously shown that two HATs, Clock and Tip60, are overexpressed in cisplatin-resistant cells and are involved in drug resistance (10,11). HATs are categorized into two families, MYST (MOZ, YBF2/SAS3, SAS2, and Tip60) and GNAT (Gcn5-related N-acetyltransferases).…”

“…Clock regulates glutathione biosynthesis by activating ATF4 and induces multidrug resistance (10). Tip60 is a Clock target gene and modulates the expression of DNA repair genes (11). Thus, these HATs are directly involved in drug resistance.…”

“…Several mechanisms are involved in the acquisition of cisplatin resistance (3), which include reduced drug accumulation (4,5), increased production of cellular thiol (6,7) and augmented DNA repair activity (8,9). We have recently reported that two histone acetyltransferases (HAT), Clock and Tip60, are overexpressed in cisplatin-resistant cells (10,11). Clock regulates glutathione biosynthesis by activating ATF4 and induces multidrug resistance (10).…”

Sensitivity of doxorubicin-resistant cells to sorafenib: Possible role for inhibition of eukaryotic initiation factor-2α phosphorylation

“…Although anticancer agents decrease patient tumor burdens and expand life expectancy, nonresponsiveness or development of chemotherapy resistance are major obstacles for effective cancer treatment. We have previously investigated mechanisms of resistance to anticancer drugs including cisplatin, vincristine, etoposide and doxorubicin (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Doxorubicin has been administered for many types of solid tumors including breast cancer, hepatocellular cancer and urothelial cancer.…”