DNA methylation-mediated epigenetic regulation of oncogenic RPS2 as a novel therapeutic target and biomarker in hepatocellular carcinoma

• Published in: Biochemical and biophysical research communications 2024-02, Vol.696, p.149453, Article 149453
• Main Authors: Abi Zamer, Batoul, Rah, Bilal, Jayakumar, Manju Nidagodu, Abumustafa, Wafaa, Hamad, Mawieh, Muhammad, Jibran Sualeh
• Format: Article
• Language: English
• Subjects: Biomarker; DNA methylation; Epigenetics; Hepatocellular carcinoma; Ribosomal protein S2; Therapeutics
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2023.149453

Ribosomal Protein S2 (RPS2) has emerged as a potential prognostic biomarker due to its involvement in key cellular processes and its altered expression pattern in certain types of cancer. However, its role in hepatocellular carcinoma (HCC) has yet to be investigated. Herein, we analyzed RPS2 mRNA expression and promoter methylation in HCC patient samples and HepG2 cells. Subsequently, loss-of-function experiments were conducted to determine the function of RPS2 in HCC cells in vitro. Our results revealed that RPS2 mRNA expression is significantly elevated, and its promoter is hypomethylated in HCC patient samples compared to controls. In addition, 5-Azacytidine treatment in HepG2 cells decreased RPS2 promoter methylation level and increased its mRNA expression. RPS2 knockdown in HepG2 cells suppressed cell proliferation and promoted apoptosis. Functional pathway analysis of genes positively and negatively associated with RPS2 expression in HCC showed enrichment in ribosomal biogenesis, translation machinery, cell cycle regulation, and DNA processing. Furthermore, utilizing drug-protein 3D docking, we found that doxorubicin, sorafenib, and 5-Fluorouracil, showed high affinity to the active sites of RPS2, and in vitro treatment with these drugs reduced RPS2 expression. For the first time, we report on DNA methylation-mediated epigenetic regulation of RPS2 and its oncogenic role in HCC. Our findings suggest that RPS2 plays a significant role in the development and progression of HCC, hence its potential prognostic and therapeutic utility. Moreover, as epigenetic changes happen early in cancer development, RPS2 may serve as a potential biomarker for tumor progression. •RPS2 expression is epigenetically modulated via DNA methylation in HCC.•Doxorubicin, sorafenib, and 5-Fluorouracil decrease RPS2 expression in HepG2 cells.•Silencing RPS2 decreases HCC carcinogenicity by promoting apoptosis.•RPS2 could serve as a therapeutic target in HCC and its promoter methylation levels could help in disease prognosis.