Wang Panpan, Mak Victor Cy, Rao Ling, Wu Qiuqiu, Zhou Yuan, Sharma Rakesh, Kwon S Chul, Cheung Lydia Wt
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Proteomics and Metabolomics Core, Centre for PanorOmic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Nat Commun. 2025 Feb 27;16(1):2042. doi: 10.1038/s41467-025-56532-3.
p85β is a regulatory subunit of the phosphoinositide 3-kinase (PI3K). Emerging evidence suggests that p85β goes beyond its role in the PI3K and is functional in the nucleus. In this study, we discover that nuclear p85β is enriched at gene loci and regulates gene transcription and that this regulatory role contributes to the oncogenic potential of nuclear p85β. A multi-omics approach reveals the physical interaction and functional cooperativity between nuclear p85β and a transcription factor BCLAF1. We observe genome-wide co-occupancy of p85β and BCLAF1 at gene targets associated with transcriptional responses. Intriguingly, the targetome includes BCLAF1 of which transcription is activated by p85β and BCLAF1, indicating a positive autoregulation. While BCLAF1 recruits p85β to BCLAF1 loci, p85β facilitates the assembly of BCLAF1, the scaffold protein TRIM28 and the zinc finger transcription factor ZNF263, which together act in concert to activate BCLAF1 transcription. Collectively, this study provides functional evidence and mechanistic basis to support a role of nuclear p85β in modulating gene transcription.
p85β是磷酸肌醇3激酶（PI3K）的一个调节亚基。新出现的证据表明，p85β不仅在PI3K中发挥作用，在细胞核中也具有功能。在本研究中，我们发现细胞核中的p85β在基因位点富集并调节基因转录，且这种调节作用有助于细胞核p85β的致癌潜力。一种多组学方法揭示了细胞核p85β与转录因子BCLAF1之间的物理相互作用和功能协同性。我们观察到p85β和BCLAF1在全基因组范围内共同占据与转录反应相关的基因靶点。有趣的是，靶点组包括其转录由p85β和BCLAF1激活的BCLAF1，这表明存在正自调节。当BCLAF1将p85β招募到BCLAF1基因位点时，p85β促进了BCLAF1、支架蛋白TRIM28和锌指转录因子ZNF263的组装，它们共同协同作用以激活BCLAF1转录。总体而言，本研究提供了功能证据和机制基础，以支持细胞核p85β在调节基因转录中的作用。
