Transcriptional Regulation of XPR1 by ETS1 in Hepatocellular Carcinoma: A Link Between EMT and Phosphate Metabolism

Metabolic adaptation is a hallmark of cancer, with phosphate homeostasis playing a crucial role in supporting tumor growth and survival. SLC53A1, xenotropic and polytropic retrovirus receptor 1 (XPR1), the only known inorganic phosphate exporter in multicellular organisms, is frequently overexpressed in hepatocellular carcinoma (HCC) and associated with aggressive tumor behavior. However, its upstream regulatory mechanisms remain largely undefined. In this study, we investigated the transcriptional control of XPR1 by ETS Proto-Oncogene 1 (ETS1), a context-dependent transcription factor implicated in epithelial–mesenchymal transition and tumor progression. In silico analysis of the Eukaryotic Promoter Database (EPD) revealed several putative ETS1 binding sites within the XPR1 promoter region. Chromatin immunoprecipitation (ChIP) assays confirmed ETS1 binding to the XPR1 promoter. Furthermore, ETS1 knockdown using the lentiviral system in Sk-HEP1 and SNU398 HCC cell lines led to a significant increase in XPR1 mRNA expression by qPCR. A consistent inverse relationship between ETS1 and XPR1 expression was observed across HCC cell lines. These findings demonstrate that ETS1 acts as a transcriptional repressor of XPR1. Given XPR1’s role in phosphate efflux, ETS1-mediated suppression may limit phosphate export in early tumor stages. Notably, public transcriptomic datasets reveal reduced ETS1 and elevated XPR1 expression in advanced HCC, correlating with poor prognosis. This study identifies a novel ETS1–XPR1 regulatory axis, highlighting the convergence of transcriptional and metabolic control in HCC. Targeting this axis could offer new therapeutic opportunities in metabolically dysregulated tumors.