What question did this study set out to answer?

To identify risk scores and molecular subtypes based on chromatin regulators that predict biochemical recurrence after radical prostatectomy in prostate cancer patients.

March 15, 2026Open Access

Chromatin regulators TOP2A and PPARGC1A stratify prostate cancer risk and reveal TOP2A-driven progression via PI3K/AKT pathway

Key Points

To identify risk scores and molecular subtypes based on chromatin regulators that predict biochemical recurrence after radical prostatectomy in prostate cancer patients.
Intersected differentially expressed genes from TCGA and GEO databases with chromatin regulator-related genes.
Performed consensus clustering, risk score analysis, and functional analysis using R software.
Validated findings in vitro using DU145 and C42B prostate cancer cell lines, including TOP2A knockdown via siRNA.
TOP2A and PPARGC1A defined molecular subtypes and risk scores in prostate cancer patients.
Cluster 2 shown to have significantly shorter BCR-free survival compared to cluster 1 in TCGA and GEO datasets.
TOP2A knockdown significantly impaired cell proliferation, migration, and invasion, and suppressed the PI3K/AKT pathway.

Abstract

ObjectiveTo identify chromatin regulators (CRs)-based molecular subtypes and risk scores for accurately predicting biochemical recurrence (BCR) after radical prostatectomy (RAP) in prostate cancer (PCa) patients.MethodsDifferentially expressed genes (DEGs) between tumor and normal samples from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) databases were intersected with CR-related and prognostic genes. Consensus clustering, risk score analysis, functional analysis, immune microenvironment, m6A, and heterogeneity assessments were performed using R software. In vitro validation used DU145 and C42B PCa cell lines. Topoisomerase II alpha (TOP2A) was knocked down via siRNA. Assays included CCK-8 proliferation, colony formation, transwell migration/invasion, wound healing, and western blotting (WB) for pathway validation.ResultsTOP2A and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) defined molecular subtypes and a risk score in TCGA, validated in a GEO dataset. Cluster 2 exhibited significantly shorter BCR-free survival vs. cluster 1 in TCGA hazard ratio (HR): 2.21; 95% confidence interval (95% CI): 1.32−3.73; P=0.003), GEO (HR: 2.05; 95% CI: 1.05−4.02; P=0.010), and MSKCC2010 (HR: 5.93; 95% CI: 1.96−17.87; PTOP2A knockdown significantly impaired PCa cell proliferation, colony formation, migration, and invasion. Mechanistically, it suppressed phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) pathway activation, reducing phosphorylated PI3K and AKT levels without altering total protein.ConclusionsTOP2A and PPARGC1A effectively stratify PCa subtypes for RAP patients. TOP2A drives malignant progression via the PI3K/AKT pathway.

KI fragen

Bookmark

View Full Paper