Identification of a Novel PDRG1-EZH2-p21 Pathway Controlling Senescence and Tumor Progression in Hepatocellular...

Hepatocellular carcinoma (HCC) remains a major global health burden with limited therapeutic options and poor prognosis. PDRG1 is upregulated in several malignancies, yet its clinical relevance and mechanistic role in HCC are not fully understood. Here, we investigated the contribution of PDRG1 to HCC progression and delineated the underlying molecular mechanism. Using public datasets, patient specimens, in vitro functional assays, and subcutaneous xenograft models, we evaluated PDRG1 expression, biological functions, and downstream pathways. Transcriptome profiling, pathway enrichment analysis, rescue experiments, co-immunoprecipitation, and ChIP-qPCR were performed to define the PDRG1-EZH2-p21 axis. PDRG1 was significantly upregulated in HCC tumor tissues compared with adjacent non-tumor liver tissues and was associated with worse patient survival. Functionally, PDRG1 enhanced HCC cell proliferation, migration, invasion, colony formation, and tumor growth in vivo. RNA-seq and enrichment analyses identified cellular senescence as a prominent downstream program regulated by PDRG1. Mechanistically, PDRG1 directly interacted with EZH2, increased H3K27me3 enrichment at the p21 promoter, and suppressed p21 transcription. Restoration of p21 expression attenuated the oncogenic effects of PDRG1, whereas EZH2 overexpression rescued the impaired malignant phenotypes caused by PDRG1 knockdown. Domain-mapping further indicated that the N-terminal residues 36-70 of PDRG1 contribute to its interaction with EZH2. Collectively, our findings identify PDRG1 as a clinically relevant oncogene in HCC and reveal an epigenetic mechanism by which PDRG1 cooperates with EZH2 to repress p21 and bypass senescence. The PDRG1-EZH2-p21 axis may represent a potential biomarker and therapeutic target for HCC.