Abstract 5400: SEPHS2 loss reprograms glucose metabolism to activate the pentose phosphate pathway by stabilizing PCK1 through NAD(+)

Abstract Selenium is an essential trace mineral that plays a crucial role in metabolism, primarily through its incorporation into selenoproteins. However, whether and how selenium modulates glucose metabolism in cancer cells remains unclear. This study focuses on SEPHS2, a key enzyme in synthesizing selenoproteins, which converts hydrogen selenide into selenophosphate. We found that SEPHS2 knockout inhibits both glycolysis and oxidative phosphorylation (OXPHOS), as indicated by an seahorse assay. Interestingly, SEPHS2 loss redirects more glucose to the pentose phosphate pathway. Mechanistically, SEPHS2 knockout elevates NAD+ levels, which are essential for SIRT2/3 enzymatic activity. The increase in the activity of SIRT2/3 leads to deacetylation of PCK1, a posttranslational modification required to prevent PCK1’s ubiquitination and subsequent degradation. Thus, SEPHS2 knockout stabilizes PCK1 by reducing its ubiquitination. Since PCK1 is a key regulator of gluconeogenesis, SEPHS2 knockout promotes gluconeogenesis while reducing cellular glucose uptake, suppressing glycolysis, down-regulating oxidative phosphorylation and enhancing the pentose phosphate pathway. Collectively, our findings define the selenium-metabolizing enzyme SEPHS2 as a key regulator of glucose metabolism, guiding cancer cells in choosing between glycolysis and the pentose phosphate pathway. This study offers valuable insight into the essential role of selenium metabolism in maintaining glucose homeostasis. Citation Format: Yihuizhi Zhang, Qinhua Zhang, Weibo Zhang, Weijian Ding, Baotong Zhang, Siyuan Xia. SEPHS2 loss reprograms glucose metabolism to activate the pentose phosphate pathway by stabilizing PCK1 through NAD(+) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5400.