BRD7 is a candidate tumour suppressor gene required for p53 function.
Oncogene-induced senescence is a p53-dependent defence mechanism against uncontrolled proliferation. Consequently, many human tumours harbour p53 mutations and others show a dysfunctional p53 pathway, frequently by unknown mechanisms. Here we identify BRD7 (bromodomain-containing 7) as a protein whose inhibition allows full neoplastic transformation in the presence of wild-type p53. In human breast tumours harbouring wild-type, but not mutant, p53 the BRD7 gene locus was frequently deleted and low BRD7 expression was found in a subgroup of tumours. Functionally, BRD7 is required for efficient p53-mediated transcription of a subset of target genes. BRD7 interacts with p53 and p300 and is recruited to target gene promoters, affecting histone acetylation, p53 acetylation and promoter activity. Thus, BRD7 suppresses tumorigenicity by serving as a p53 cofactor required for the efficient induction of p53-dependent oncogene-induced senescence.
Drost
Jarno
J
The Netherlands Cancer Institute, Division of Gene Regulation, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
Mantovani
Fiamma
F
Tocco
Francesca
F
Elkon
Ran
R
Comel
Anna
A
Holstege
Henne
H
Kerkhoven
Ron
R
Jonkers
Jos
J
Voorhoeve
P Mathijs
PM
Agami
Reuven
R
Del Sal
Giannino
G
D000107:Acetylation; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D006657:Histones / Q000378:metabolism; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; C485694:BRD7 protein, human; D000092468:Bromodomain Containing Proteins; C495901:TP53 protein, human