Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response.
The acetyl-transferase Tip60 might influence tumorigenesis in multiple ways. First, Tip60 is a co-regulator of transcription factors that either promote or suppress tumorigenesis, such as Myc and p53. Second, Tip60 modulates DNA-damage response (DDR) signalling, and a DDR triggered by oncogenes can counteract tumour progression. Using E(mu)-myc transgenic mice that are heterozygous for a Tip60 gene (Htatip) knockout allele (hereafter denoted as Tip60+/- mice), we show that Tip60 counteracts Myc-induced lymphomagenesis in a haplo-insufficient manner and in a time window that is restricted to a pre- or early-tumoral stage. Tip60 heterozygosity severely impaired the Myc-induced DDR but caused no general DDR defect in B cells. Myc- and p53-dependent transcription were not affected, and neither were Myc-induced proliferation, activation of the ARF-p53 tumour suppressor pathway or the resulting apoptotic response. We found that the human TIP60 gene (HTATIP) is a frequent target for mono-allelic loss in human lymphomas and head-and-neck and mammary carcinomas, with concomitant reduction in mRNA levels. Immunohistochemical analysis also demonstrated loss of nuclear TIP60 staining in mammary carcinomas. These events correlated with disease grade and frequently concurred with mutation of p53. Thus, in both mouse and human, Tip60 has a haplo-insufficient tumour suppressor activity that is independent from-but not contradictory with-its role within the ARF-p53 pathway. We suggest that this is because critical levels of Tip60 are required for mounting an oncogene-induced DDR in incipient tumour cells, the failure of which might synergize with p53 mutation towards tumour progression.
Gorrini
Chiara
C
Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Milan 20139, Italy.
Squatrito
Massimo
M
Luise
Chiara
C
Syed
Nelofer
N
Perna
Daniele
D
Wark
Landon
L
Martinato
Francesca
F
Sardella
Domenico
D
Verrecchia
Alessandro
A
Bennett
Samantha
S
Confalonieri
Stefano
S
Cesaroni
Matteo
M
Marchesi
Francesco
F
Gasco
Milena
M
Scanziani
Eugenio
E
Capra
Maria
M
Mai
Sabine
S
Nuciforo
Paolo
P
Crook
Tim
T
Lough
John
J
Amati
Bruno
B
D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D004249:DNA Damage; D016147:Genes, Tumor Suppressor; D016259:Genes, myc / Q000235:genetics; D006579:Heterozygote; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D008822:Mice, Transgenic; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics*; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D016274:Oncogene Protein p55(v-myc); D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5