REEP6 promotes colorectal cancer glycolysis and tumorigenesis through PRMT5-mediated PGAM1 arginine methylation

Tuo Wang; Dongsheng Zhang; Chi Jin; Hengjie Xu; Hongxu Nie; Ye Wang; Chuan Zhang; Yifei Feng; Junwei Tang; Yueming Sun

doi:10.1016/j.apsb.2025.10.025

REEP6 promotes colorectal cancer glycolysis and tumorigenesis through PRMT5-mediated PGAM1 arginine methylation

Acta Pharm Sin B. 2026 Feb;16(2):948-965. doi: 10.1016/j.apsb.2025.10.025. Epub 2025 Oct 24.

Authors

Tuo Wang^{1

2

3}, Dongsheng Zhang^{1

2

3}, Chi Jin^{1

2

3}, Hengjie Xu^{1

2

3}, Hongxu Nie^{1

2

3}, Ye Wang^{1

2

3}, Chuan Zhang^{1

2

3}, Yifei Feng^{1

2

3}, Junwei Tang^{1

2

3}, Yueming Sun^{1

2

3

4}

Affiliations

¹ Department of General Surgery, Colorectal Institute of Nanjing Medical University, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
² Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing 210029, China.
³ Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, China.
⁴ The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian 223800, China.

Abstract

Metabolic reprogramming is a notable hallmark of cancer biology, especially aerobic glycolysis. Some clinical trials attempt to target cancer metabolism to develop therapeutic agents. However, the results have been not satisfactory. Here, we report that REEP6 is significantly upregulated and promotes glycolysis and tumorigenesis in CRC. Moreover, REEP6, as a molecular scaffolder, bridges the PRMT5-PGAM1 complex, which enhances the PRMT5-mediated symmetric dimethylarginine (SDMA) of PGAM1 at R40. The methylated PGAM1 possesses dramatically enhanced enzymatic activity and therefore boosts glycolytic flux in CRC cells. More than that, our results showed that combined treatment with specific shRNA and inhibitors exhibits synergistic anti-tumor efficacy in CRC, which may shed light on the development of a promising therapy in CRC.

Keywords: Aerobic glycolysis; Colorectal cancer; Metabolic reprogramming; PGAM1; PRMT5; REEP6; Symmetric dimethylarginine; Tumorigenesis.