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Abstract
Sepiapterin reductase plays an enzymatic role in the biosynthesis of tetrahydrobiopterin, which is reported in limited studies to regulate the progression of several tumors. However, the role of sepiapterin reductase in hepatocellular carcinoma remains largely unknown. Here, we found that sepiapterin reductase was frequently highly expressed in human hepatocellular carcinoma, which was significantly associated with higher T stage, higher tumor node metastasis stage, and even shorter survival of hepatocellular carcinoma patients. Furthermore, cell and animal experiments showed that sepiapterin reductase depletion inhibited cancer cell proliferation and promoted cancer cell apoptosis. Importantly, the results suggested that sepiapterin reductase enzymatic activity was not necessary for the progression of hepatocellular carcinoma, based on the comparison between SMMC-7721 and SMMC-7721 containing sepiapterin reductase mutant. Moreover, we showed that sepiapterin reductase regulated the development of hepatocellular carcinoma via the FoxO3a/Bim-signaling pathway. Collectively, our study suggests that sepiapterin reductase controls hepatocellular carcinoma progression via FoxO3a/Bim signaling in a nonenzymatic manner, which provides a potential prognostic factor and therapeutic strategy for hepatocellular carcinoma.
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1 China Pharmaceutical University, Jiangsu Key Laboratory of Drug Screening, Nanjing, China (GRID:grid.254147.1) (ISNI:0000 0000 9776 7793)
2 Hubei University of Chinese Medicine, School of Pharmacy, Wuhan, China (GRID:grid.257143.6) (ISNI:0000 0004 1772 1285)
3 Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai, China (GRID:grid.452930.9) (ISNI:0000 0004 1757 8087)
4 The Second Affiliated Hospital of Nanchang University, Department of Neurosurgery, Nanchang, China (GRID:grid.412455.3)
5 ShanghaiTech University, School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2)
6 Peking Union Medical College, Institute of Dermatology, Chinese Academy of Medical Science, Nanjing, China (GRID:grid.440637.2)
7 China Pharmaceutical University, Jiangsu Key Laboratory of Drug Screening, Nanjing, China (GRID:grid.254147.1) (ISNI:0000 0000 9776 7793); Chinese Academy of Sciences, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309)