SphK2 confers 5-fluorouracil resistance to colorectal cancer via upregulating H3K56ac-mediated DPD expression

• Published in: Oncogene 2020-07, Vol.39 (29), p.5214-5227
• Main Authors: Zhang, Yu-Hang, Shi, Wen-Na, Wu, Shu-Hua, Miao, Rong-Rong, Sun, Shi-Yue, Luo, Dong-Dong, Wan, Sheng-Biao, Guo, Zhi-Kun, Wang, Wen-Yu, Yu, Xin-Feng, Cui, Shu-Xiang, Qu, Xian-Jun
• Format: Article
• Language: English
• Subjects: 101/47; 13/1; 13/105; 13/109; 5-Fluorouracil; 59/5; 631/154/155; 631/67/1059/2326; 631/67/1504/1885; 64/60; 82/58; 82/80; Alanine; Analysis; Animal models; Animals; Apoptosis; Cancer; Cell Biology; Cell culture; Chemoresistance; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Dihydrouracil Dehydrogenase (NADP) - metabolism; Drug Resistance, Neoplasm - genetics; Fluorouracil; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Human Genetics; Humans; Internal Medicine; Lipid metabolism; Medicine; Medicine & Public Health; Mice; Oncology; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Reporter gene; Tumor cell lines; Tumors; Up-Regulation; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1352-y

Aberrant sphingolipid metabolism has been implicated in chemoresistance, but the underlying mechanisms are still poorly understood. Herein we revealed a previously unrecognized mechanism of 5-fluorouracil (5-FU) resistance contributed by high SphK2-upregulated dihydropyrimidine dehydrogenase (DPD) in colorectal cancer (CRC), which is evidenced from human CRC specimens, animal models, and cancer cell lines. TMA samples from randomly selected 60 CRC specimens firstly identified the clinical correlation between high SphK2 and increased DPD ( p