Targeting POLR1A induces apoptosis and inhibits hepatocellular carcinoma proliferation through upregulation of IFI27 transcription

Objective Evasion of apoptosis and uncontrolled proliferation are hallmarks of cancer. RNA Polymerase I Subunit A (POLR1A), the catalytic core of RNA Polymerase I, is highly expressed in various tumors and exerts a cancer-promoting effect; however, its expression in hepatocellular carcinoma remain unclear.This study aims to delineate the oncogenic role, regulatory mechanism, and therapeutic targeting of POLR1A in Hepatocellular Carcinoma (HCC). Methods POLR1A expression and its prognostic significance were analyzed using TCGA data and clinical tissues. Functional roles of POLR1A in proliferation and apoptosis were assessed in HCC cell lines following knockdown and overexpression. The POLR1A inhibitor BMH-21 was evaluated for its anti-tumor effects. Mechanistically, RNA-seq identified downstream targets, ChIP-qPCR and dual-luciferase assays elucidated transcriptional regulation. Protein stability was investigated via CHX chase, Co-IP, ubiquitination assays, and MG-132 treatment. Results POLR1A was significantly overexpressed in HCC tissues, correlating with advanced T stage, vascular invasion, and poor survival, serving as an independent prognostic factor. POLR1A knockdown induced apoptosis and suppressed proliferation, while its overexpression exerted opposite effects. BMH-21 recapitulated the pro-apoptotic and anti-proliferative phenotypes. POLR1A transcriptionally repressed the pro-apoptotic gene IFI27 by upregulating HDAC1, which bound the IFI27 promoter. Furthermore, the deubiquitinase USP36 interacted with and stabilized POLR1A by removing K48-linked ubiquitin chains, thereby inhibiting its proteasomal degradation. The interaction was mapped to POLR1A (aa 1156–1720) and USP36 (aa 1-423). Conclusions We demonstrate that the POLR1A-IFI27 axis drives HCC tumorigenesis through apoptosis suppression. Targeting this axis holds translational promise, as the POLR1A inhibitor BMH-21 exhibits potent anti-tumor effects in preclinical models, supporting its further clinical development.