PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth

• Published in: Nature communications 2019-12, Vol.10 (1), p.5800-15, Article 5800
• Main Authors: Cai, Weijia, Su, Liya, Liao, Lili, Liu, Zongzhi Z., Langbein, Lauren, Dulaimi, Essel, Testa, Joseph R., Uzzo, Robert G., Zhong, Zhijiu, Jiang, Wei, Yan, Qin, Zhang, Qing, Yang, Haifeng
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/109; 13/51; 13/89; 13/95; 38; 38/77; 38/88; 631/45; 631/45/611; 631/67; 631/67/589; 631/67/589/1588; 64; 64/60; Acetylation; Animals; Cancer; Cell Line, Tumor; Crosstalk; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; HEK293 Cells; Humanities and Social Sciences; Humans; Kidney - pathology; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Lysine; Lysine - metabolism; Male; Mice; multidisciplinary; Mutation; p53 Protein; Promoter Regions, Genetic; Protein Binding - genetics; Protein Domains - genetics; Science; Science (multidisciplinary); Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13608-1

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. Acetylation of p53 is critical for its transcriptional activity and its tumour suppressive function. Here, the authors show that PBRM1 is a reader protein for p53′s C-terminal domain acetylation on lysine 382 through its bromodomain 4 and that mutations in this domain leads to compromised tumour suppressive function and renal tumour growth.