The acetyltransferase Tip60 contributes to mammary tumorigenesis by modulating DNA repair

Abstract

The acetyltransferase Tip60/Kat5 acetylates both histone and non-histone proteins, and is involved in a variety of biological processes. By acetylating p53, Tip60 controls p53-dependent transcriptional activity and so is implicated as a tumor suppressor. However, many breast cancers with low Tip60 also show p53 mutation, implying that Tip60 has a tumor suppressor function independent of its acetylation of p53. Here, we show in a p53-null mouse model of sporadic invasive breast adenocarcinoma that heterozygosity for Tip60 deletion promotes mammary tumorigenesis. Low Tip60 reduces DNA repair in normal and tumor mammary epithelial cells, both under resting conditions and following genotoxic stress. We demonstrate that Tip60 controls homologous recombination (HR)-directed DNA repair, and that Tip60 levels correlate inversely with a gene expression signature associated with defective HR-directed DNA repair. In human breast cancer data sets, Tip60 mRNA is downregulated, with low Tip60 levels correlating with p53 mutations in basal-like breast cancers. Our findings indicate that Tip60 is a novel breast tumor suppressor gene whose loss results in genomic instability leading to cancer formation.

The haploinsufficient tumor suppressor Tip60 negatively regulates the oncogenic Aurora B kinase

“…We propose that widespread Tip60 downregulation in cancers favour the deregulated increase in the overall activity of AurkB in tumor cells that may act as a causative factor for the associated alterations of p53 or c-Myc pathways. Furthermore, as earlier studies elucidate the direct links between Tip60 and genomic aberrations (Bassi C et al 2016), it is worthwhile to study if any of such effects are mediated by the altered activities of AurkB. acetylated with Tip60 or mock acetylated (control) in vitro.…”

Chemical Biology Approaches for Investigating the Functions of Lysine Acetyltransferases

“…[62] TheM YST family members are also linked with av ariety of disease processes. [65] In brief,t he increased understanding of major KATs in various diseases highlights their distinction as new drug targets and brings the topic of chemical regulation of KATa ctivity to the forefront of pharmaceutical research. [64] Inhibition of Tip60 activity suppresses the tumorigenesis and sensitizes tumor cells to anticancer agents.…”

Untersuchung der epigenetischen Funktionen von Lysin‐Acetyltransferasen mit Methoden der chemischen Biologie

“…Die PCAF/GCN5-vermittelte H3K9-Acetylierung ist beim wirkstoffresistenten Brustkarzinom um zwei Grçßenordnungen erhçht. [65] Zusammenfassend unterstreicht das bessere Verständnis der wesentlichen KATs in verschiedenen Erkrankungen ihre Besonderheit als neue Angriffsziele fürW irkstoffe und stellt die chemische Regu-lation der KAT-Aktivitäti nd en Mittelpunkt der pharmazeutischen Forschung. [63] Tip60, ein erster Vertreter der MYST-Familie,i st am Androgen-vermittelten Signalweg sowie der Proliferation von kastrationsresistentem Prostatakrebs beteiligt.…”

“…[64] Die Hemmung der Tip60-Aktivitätu nterdrückt die Tu morgenese und sensibilisiert Tu morzellen fürA ntikrebsmittel. [65] Zusammenfassend unterstreicht das bessere Verständnis der wesentlichen KATs in verschiedenen Erkrankungen ihre Besonderheit als neue Angriffsziele fürW irkstoffe und stellt die chemische Regu-lation der KAT-Aktivitäti nd en Mittelpunkt der pharmazeutischen Forschung.…”