Mutations truncating the EP300 acetylase in human cancers

Abstract

The EP300 protein is a histone acetyltransferase that regulates transcription via chromatin remodelling and is important in the processes of cell proliferation and differentiation. EP300 acetylation of TP53 in response to DNA damage regulates its DNA-binding and transcription functions. A role for EP300 in cancer has been implied by the fact that it is targeted by viral oncoproteins, it is fused to MLL in Leukaemia and two missense sequence alterations in EP300 were identified in epithelial malignancies. Nevertheless, direct demonstration of the role of EP300 in tumorigenesis by inactivating mutations in human cancers has been lacking. Here we describe EP300 mutations, which predict a truncated protein, in 6(3%) of 193 epithelial cancers analysed. Of these six mutations, two were in primary tumours (a colorectal cancer and a breast cancer) and four were in cancer cell lines (colorectal, breast and pancreatic). In addition, we identified a somatic in-frame insertion in a primary breast cancer and missense alterations in a primary colorectal cancer and two cell lines (breast and pancreatic). Inactivation of the second allele was demonstrated in five of six cases with truncating mutations and in two other cases. Our data show that EP300 is mutated in epithelial cancers and provide the first evidence that it behaves as a classical tumour-suppressor gene.

The miR-106b∼25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300

“…43 In addition, somatic mutations in EP300 have been identified in several malignancies. 44 Importantly, EP300-deficient colon carcinoma cells show phenotypic changes characteristic of EMT, 45 in line with the results reported here. The involvement of miRs in drug resistance, CSCs (cells originated from adult stem cells, which have acquired tumorigenic properties and drive tumor growth and progression because of their unlimited proliferative potential), and EMT is now well established.…”

Absence of p300 induces cellular phenotypic changes characteristic of epithelial to mesenchyme transition

“…Mutations in p300/CBP have been found in a number of human cancers. Bi-allelic somatic mutations in the p300 gene have been identified in gastric, colon and breast cancers (primary tumours and cancer cell lines), and some of these mutations clearly result in inactivated or truncated protein products (Muraoka et al, 1996;Gayther et al, 2000;Ozdag et al, 2002). While this gave rise to the view that p300 could function as a classical tumour suppressor, it is still unclear how a loss of p300 and CBP could contribute to tumorigenesis (Goodman and Smolik, 2000).…”

Mutation analysis of CBP and PCAF reveals rare inactivating mutations in cancer cell lines but not in primary tumours

“…In colorectal and gastric carcinomas two somatic P300 missense mutations coupled to deletion of the second allele of the gene were identified (Muruoka et al, 1996). The role of P300 as a tumour suppressor gene was later confirmed with the identification of truncating, insertion and missense mutations in primary tumours and cancer cell lines, associated with inactivation of the second allele (Gayther et al, 2000). In this study we screened the whole coding sequence and intron -exon boundaries of both CBP and PCAF for somatic mutations in a series of human primary tumours and cancer cell lines.…”