A study of the functional roles of nuclear p85β in ovarian cancer

Abstract

Ovarian cancer, the most lethal gynecological malignancy, is characterized by frequent gene copy number alterations, including amplification of PIK3R2. PIK3R2 encodes the regulatory subunit p85β of the class IA phosphoinositide 3-kinase. Although PIK3R2 amplification is associated with poor prognosis of ovarian cancer, the oncogenic mechanisms driven by p85β, particularly its nuclear functions, remain poorly understood. This study comprehensively characterized the transcriptional regulatory landscape governed by nuclear p85β and elucidated its role in promoting ovarian cancer progression. By engineering a nuclear export signal fused to p85β, a loss-of-function approach was employed and the data demonstrated that nuclear localization of p85β contributes to its oncogenic activity. Integrative multi-omics analyses, including transcriptomics, proteomics, interactomics, and cistromics, identified BCL2-Associated Transcription Factor 1 (BCLAF1) as a transcriptional target and a binding partner of p85β in the nucleus. Critically, p85β and BCLAF1 co-bind to chromatin regions. One of the p85β and BCLAF1 co-regulated genes is BCLAF1. The ability of BCLAF1 to increase transcription of its own gene indicates an auto-regulation. Functional assays confirmed that BCLAF1 is oncogenic and mediates the oncogenicity of p85β. The other p85β and BCLAF1 co-bound target genes are enriched in the cell proliferation and migration pathways, including CCND1, ADAMTS1, and ALCAM, further linking the p85β-BCLAF1 axis to cancer progression. Moreover, mechanistic investigations revealed that p85β promotes the assembly of a cooperative transcriptional complex containing BCLAF1, TRIM28, and ZNF263. This complex co-occupies the BCLAF1 gene locus and induces BCLAF1 transcription. Apart from BCLAF1, the cooperativity of p85β/ BCLAF1/TRIM28/ZNF263 in transcription could be demonstrated using another proof-of-concept gene, CCDC85B, which is a gene that promotes ovarian cancer cell proliferation and invasion. Collectively, this study establishes nuclear p85β as a transcriptional cofactor that cooperates with BCLAF1, TRIM28, and ZNF263 to drive oncogenic gene expression in ovarian cancer. These findings identify key components of the p85β-driven transcriptional network as potential diagnostic biomarkers and therapeutic targets, offering potential avenues for the development of targeted interventions in PIK3R2-amplified ovarian cancer.