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

Year 2025, Volume: 11 Issue: 4, 359 - 368, 31.12.2025

İrem Yalım Camcı

https://doi.org/10.28979/jarnas.1758996

Abstract

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.

Keywords

SLC53A1 , xenotropic and polytropic retrovirus receptor 1 (XPR1) , ETS Proto-Oncogene 1 (ETS1) , Chromatin immunoprecipitation (ChIP) , Hepatocellular carcinoma (HCC)

Ethical Statement

No approval from the Board of Ethics is required.

Supporting Institution

Gebze Technical University

Project Number

No funding

Thanks

The author would like to thank Prof. Dr. Tamer Yağcı for kindly allowing to utilize his laboratory infrastructure.

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