Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2026
Chromatin regulators TOP2A and PPARGC1A stratify prostate cancer risk and reveal TOP2A-driven progression via PI3K/AKT pathway.
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Wang Zhipeng, Wang Jie, Chen Shuang, Wu Ruicheng, Tuo Zhouting, Ye Luxia, Yoo Koo Han, Li Dengxiong, Jin Xiaodong, Xiong Wei, Feng Dechao
Аннотация
OBJECTIVE: To 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.
METHODS: Differentially 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.
RESULTS: TOP2A 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; P<0.001). Similar survival differences were observed between high- and low-risk groups (defined by the median risk score). Cluster 2 showed greater tumor heterogeneity and higher m6A gene expression. Gene set variation analysis (GSVA) revealed downregulated cell-cycle pathways in cluster 2, alongside suppressed tumor-infiltrating immune cells. TOP2A 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.
CONCLUSIONS: TOP2A and PPARGC1A effectively stratify PCa subtypes for RAP patients. TOP2A drives malignant progression via the PI3K/AKT pathway.
METHODS: Differentially 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.
RESULTS: TOP2A 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; P<0.001). Similar survival differences were observed between high- and low-risk groups (defined by the median risk score). Cluster 2 showed greater tumor heterogeneity and higher m6A gene expression. Gene set variation analysis (GSVA) revealed downregulated cell-cycle pathways in cluster 2, alongside suppressed tumor-infiltrating immune cells. TOP2A 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.
CONCLUSIONS: TOP2A and PPARGC1A effectively stratify PCa subtypes for RAP patients. TOP2A drives malignant progression via the PI3K/AKT pathway.