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

Weijia Cai, Liya Su, Lili Liao, Zongzhi Z. Liu, Lauren Langbein, Essel Dulaimi, Joseph R. Testa, Robert G. Uzzo, Zhijiu Zhong, Wei Jiang, Qin Yan, Qing Zhang () and Haifeng Yang ()
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Weijia Cai: Thomas Jefferson University
Liya Su: Thomas Jefferson University
Lili Liao: Thomas Jefferson University
Zongzhi Z. Liu: Yale University
Lauren Langbein: Thomas Jefferson University
Essel Dulaimi: Fox Chase Cancer Center
Joseph R. Testa: Fox Chase Cancer Center
Robert G. Uzzo: Fox Chase Cancer Center
Zhijiu Zhong: Thomas Jefferson University
Wei Jiang: Thomas Jefferson University
Qin Yan: Yale University
Qing Zhang: University of North Carolina at Chapel Hill
Haifeng Yang: Thomas Jefferson University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13608-1

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