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BRD7 Is a Candidate Tumour Suppressor Gene Required for P53 Function

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BRD7 Is a Candidate Tumour Suppressor Gene Required for P53 Function ARTICLES BRD7 is a candidate tumour suppressor gene required for p53 function Jarno Drost1,8, Fiamma Mantovani2,3,8, Francesca Tocco2,3, Ran Elkon1, Anna Comel2,3, Henne Holstege4, Ron Kerkhoven5, Jos Jonkers4, P. Mathijs Voorhoeve1,7,9, Reuven Agami1,6,9 and Giannino Del Sal2,3,9 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. The p53 tumour suppressor is an essential mediator of the cellular response performed a loss-of-function screen in primary human BJ fibrob- triggered by oncogene activation, which causes a permanent cell-cycle lasts expressing hTERT and 4-OH-tamoxifen (4-OHT)-inducible arrest termed oncogene-induced senescence (OIS). OIS provides an impor- oncogenic H-RasV12 (BJ/ET/RasV12ER cells7). We have shown previ- tant barrier to tumour development in vivo1–3, and work in animal models ously that loss of p53 in primary human fibroblasts accelerates cell suggests that this may represent the major mechanism of the tumour sup- proliferation and contributes to cellular transformation8. Whereas pressive activity of p53 (ref. 4). Thus, interference with OIS by inhibiting the acceleration of cell proliferation was mediated through p14ARF, the p53 tumour suppressor pathway allows cells to continue to proliferate cellular transformation was independent of it. Therefore, to focus on in the presence of active oncogenes, leading to an increased frequency of genes acting in the transformation process, we performed our screen tumour formation. This is reflected in the appearance of mutations in p53 in BJ/ET/RasV12ER cells in which p14ARF was knocked down (Fig. 1a). in as many as 50% of human tumours (ref. 5). In most other cases, in which Nineteen outliers were selected (Supplementary Information, the p53 gene is wild-type, genetic lesions in components of the p53 pathway Table S1). Validation with additional knockdowns targeting these are found interfering with its activation. A classical example is the increased genes indentified several that conferred a growth advantage on BJ/ turnover or sequestration of the p53 protein itself through, for example, ET cells expressing RasV12, all targeting the same gene, BRD7 (Fig 1b; overexpression of HDM2 (ref. 5). Other examples involve the loss of gene Supplementary Information, Fig. S1). There was a correlation products that are required for full activation of the p53 protein, or inhibi- between BRD7 knockdown efficiency and functionality (Fig. 1b), tion of p53 function downstream of its activation6,7. However, for many and no changes in p53 and RasV12 expression levels were observed tumours that retain wild-type p53 the genetic alterations leading to func- (Fig. 1c). These results suggest that inhibition of BRD7 expression tional impairment of the tumour suppressive response are not defined. enables primary human BJ cells to continue proliferating in the pres- ence of oncogenic RasV12, implying that BRD7 is involved in OIS. RESULTS Next, we characterized the effect of BRD7 loss on several well-estab- A loss of function screen for genes required for p53-dependent lished markers of OIS, including flat cell morphology, expression of senes- OIS identifies BRD7 cence-associated β-galactosidase, and formation of senescence-associated To identify genes in the p53 pathway that are required for OIS, we heterochromatin foci. In comparison with control cells, a marked decrease 1The Netherlands Cancer Institute, Division of Gene Regulation, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. 2Laboratorio Nazionale CIB, Area Science Park, Padriciano 99, 34012 Trieste, Italy. 3Dipartimento di Scienze della Vita, Università di Trieste, 34100 Trieste, Italy. 4The Netherlands Cancer Institute, Division of Molecular Biology, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. 5The Netherlands Cancer Institute, Central Microarray Facility, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. 6Center for Biomedical Genetics, The Netherlands. 7Present address: Duke-NUS Graduate Medical School, Division of Cancer and Stem Cell Biology, 8 College Road, Singapore 169857. 8These authors contributed equally to this work. 9Correspondence should be addressed to P.M.V., R.A. or G.D.S. (e-mail: [email protected]; [email protected]; [email protected]). Received 14 December 2009; accepted 17 February 2010; published online 14 March 2010; DOI:10.1038/ncb2038 380 NATURE CELL BIOLOGY VOLUME 12 | NUMBER 4 | APRIL 2010 © 2010 Macmillan Publishers Limited. All rights reserved. ARTICLES a KD V12 hTERT RasV12 b BJ/ET-p14 + Ras 3 pRS-BRD7 1 Primary cells Proliferation pRS-BRD7 2 2 pRS-BRD7 3 p53 pRS-BRD7 4 1 pRS-p53 2 advantage V12 hTERT Ras pRS-Control Cumulative growth 0 0246810 Primary cells Oncogene-induced senescence Time (days) 1.5 p14 RasV12 1.0 hTERT BRD7 0.5 shRNA Culture for Primary cells Barcode array mRNA levels library 3 weeks Relative 0 p14 Control1 234 BRD7KD cd20 18 BRD7 16 14 p53 12 10 Actin 8 (percentage) 6 RasV12 4 -Galactosidase-positive cells pRS: C 1 4B p53B C 1 4B p53B β 2 RasV12 0 pRS: Control BRD7 1 BRD7 4 p53 2 e pRS-Control pRS-BRD7 1 pRS-BRD7 4 100 80 60 40 20 + 4-OHT (RasV12) 0 SAHFs-positive cells (percentage) pRS: Control BRD7 1 BRD7 4 + 4-OHT (RasV12) Figure 1 A genetic screen for genes required for OIS identifies BRD7. (a) 3 days and then harvested; western blot analysis was performed to detect Schematic representation of OIS and the setup of the loss-of-function BRD7, p53, RasV12 and actin (loading control). Uncropped images of blots screen. (b) GFP-growth competition assays of BJ/ET/p14ARF-KD/RasV12ER cells are shown in Supplementary Information, Fig. S15. (d) Cells from c were transduced with the indicated pRetrosuper (pRS) knockdown vectors and cultured in the presence of 4-OHT for 10 days and stained to detect cells cultured in the presence of 4-OHT (+RasV12). An accompanying quantitative that were positive for senescence-associated β-galactosidase. Graphs show RT–PCR for BRD7 mRNA expression shows the functionality of the BRD7 means and s.d. for three independent experiments. (e) Cells from c were knockdown vectors. Graphs show means and s.d. for three independent cultured in the presence of 4-OHT for 10 days and senescence-associated experiments. (c) BJ/ET/RasV12ER cells were transduced with the indicated heterochromatin foci were revealed by Hoechst staining. Scale bars, 20 µM. knockdown vectors and cultured in the absence or presence of 4-OHT for Graphs show means and s.d. for three independent experiments. in all senescence markers was observed in RasV12-expressing BRD7- (Supplementary Information, Fig. S3b). No change in appearance or per- knockdown (BRD7KD) and p53-knockdown (p53KD) cells (Fig. 1d, e; sistence of γ-H2AX foci during recovery from DNA damage was observed Supplementary Information, Fig. S2a). No significant changes in BRD7 in BJ/ET cells expressing BRD7KD (Supplementary Information, Fig. S4), messenger RNA and protein levels were observed on expression of RasV12 implying that BRD7 does not directly influence the DNA damage response. (data not shown; Fig. 1c), and in addition the nuclear localization of BRD7 Re-expression of short hairpin RNA (shRNA)-resistant BRD7 in RasV12- did not change (Supplementary Information, Fig. S3b). Further, BRD7 expressing BJ/ET-BRD7KD cells significantly inhibited cell growth, showing did not co-localize with senescence-associated heterochromatin foci that BRD7 is indeed the functional factor in these assays (Supplementary NATURE CELL BIOLOGY VOLUME 12 | NUMBER 4 | APRIL 2010 381 © 2010 Macmillan Publishers Limited. All rights reserved. ARTICLES abc BJ/ET BJ/ET + RasV12 BJ/ET-p53KD 8 pRS-Control 6 3 pRS-BRD7 1 pRS-BRD7 4 5 6 pRS-p14 1 4 2 pRS-p53 2 3 4 pRS-p16 4 2 1 2 1 0 0 0 0510 0510 0510 def KD V12 KD KD V12 8 BJ/ET-p53 + Ras 3 BJ/ET-BRD7 6 BJ/ET-BRD7 + Ras 6 2 4 Cumulative growth advantage 4 1 2 2 0 0 0 0510 0510 0510 Time (days) Time (days) Time (days) Figure 2 Genetic interaction of BRD7 with the p53 pathway. GFP growth absence (a, c, e) or presence (b, d, f) of 4-OHT: (a) BJ/ET, (b) BJ/ET + RasV12, competition assays of BJ/ET/RasV12ER cells with the indicated genetic (c) BJ/ET-p53KD, (d) BJ/ET-p53KD + RasV12, (e) BJ/ET-BRD7KD, (f) BJ/ET- backgrounds and expressing the indicated pRS-GFP vectors cultured in the BRD7KD + RasV12. Information, Fig. S1c, d). Finally, the requirement of BRD7 for OIS is not In vitro binding assays with a maltose-binding protein (MBP)–BRD7 specific to RasV12-induced senescence, because cells expressing BRD7KD fusion protein and several deletion mutants of p53 mapped the region were also less efficient in inducing senescence on overexpression of c-Myc of binding of p53 to BRD7 to its C-terminal domain (residues 363–393; (ref. 9) (Supplementary Information, Fig. S2b–d). Taken together, these Fig. 3b). Pull-down assays indicated that p53 interacts with the amino- results indicate that BRD7 is required for p53-dependent OIS.
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