TY - JOUR
T1 - PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth
AU - Cai, Weijia
AU - Su, Liya
AU - Liao, Lili
AU - Liu, Zongzhi Z.
AU - Langbein, Lauren
AU - Dulaimi, Essel
AU - Testa, Joseph R.
AU - Uzzo, Robert G.
AU - Zhong, Zhijiu
AU - Jiang, Wei
AU - Yan, Qin
AU - Zhang, Qing
AU - Yang, Haifeng
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - p53 acetylation is indispensable for its transcriptional activity and tumor suppressive function. However, the identity of reader protein(s) for p53 acetylation remains elusive. PBRM1, the second most highly mutated tumor suppressor gene in kidney cancer, encodes PBRM1. Here, we identify PBRM1 as a reader for p53 acetylation on lysine 382 (K382Ac) through its bromodomain 4 (BD4). Notably, mutations on key residues of BD4 disrupt recognition of p53 K382Ac. The mutation in BD4 also reduces p53 binding to promoters of target genes such as CDKN1A (p21). Consequently, the PBRM1 BD4 mutant fails to fully support p53 transcriptional activity and is defective as a tumor suppressor. We also find that expressions of PBRM1 and p21 correlate with each other in human kidney cancer samples. Our findings uncover a tumor suppressive mechanism of PBRM1 in kidney cancer and provide a mechanistic insight into the crosstalk between p53 and SWI/SNF complexes.
AB - p53 acetylation is indispensable for its transcriptional activity and tumor suppressive function. However, the identity of reader protein(s) for p53 acetylation remains elusive. PBRM1, the second most highly mutated tumor suppressor gene in kidney cancer, encodes PBRM1. Here, we identify PBRM1 as a reader for p53 acetylation on lysine 382 (K382Ac) through its bromodomain 4 (BD4). Notably, mutations on key residues of BD4 disrupt recognition of p53 K382Ac. The mutation in BD4 also reduces p53 binding to promoters of target genes such as CDKN1A (p21). Consequently, the PBRM1 BD4 mutant fails to fully support p53 transcriptional activity and is defective as a tumor suppressor. We also find that expressions of PBRM1 and p21 correlate with each other in human kidney cancer samples. Our findings uncover a tumor suppressive mechanism of PBRM1 in kidney cancer and provide a mechanistic insight into the crosstalk between p53 and SWI/SNF complexes.
KW - Acetylation
KW - Animals
KW - Cell Line, Tumor
KW - Cyclin-Dependent Kinase Inhibitor p21/genetics
KW - DNA-Binding Proteins/genetics
KW - Gene Expression Regulation, Neoplastic
KW - Gene Knockout Techniques
KW - HEK293 Cells
KW - Humans
KW - Kidney Neoplasms/genetics
KW - Kidney/pathology
KW - Lysine/metabolism
KW - Male
KW - Mice
KW - Mutation
KW - Promoter Regions, Genetic
KW - Protein Binding/genetics
KW - Protein Domains/genetics
KW - Transcription Factors/genetics
KW - Tumor Suppressor Protein p53/genetics
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=85076900246&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000509780300004&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1038/s41467-019-13608-1
DO - 10.1038/s41467-019-13608-1
M3 - Article
C2 - 31863007
SN - 2041-1723
VL - 10
SP - 5800
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5800
ER -