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Abstract：
Fatty acid synthesis has been extensively investigated as a therapeutic target in cancers, including colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in CRC, and therapeutic approaches of targeting this enzyme are currently being tested in multiple clinical trials. However, the mechanisms behind the pro-oncogenic action of FASN are still not completely understood. Here, for the first time, we show that overexpression of FASN increases the expression of glutamine-fructose-6-phosphate transaminase 1 (GFPT1) and O-linked N-acetylglucosamine transferase (OGT), enzymes involved in hexosamine metabolism, and the level of O-GlcNAcylation in vitro and in vivo. Consistently, expression of FASN significantly correlates with expression of GFPT1 and OGT in human CRC tissues. shRNA-mediated downregulation of GFPT1 and OGT inhibits cellular proliferation and the level of protein O-GlcNAcylation in vitro, and knockdown of GFPT1 leads to a significant decrease in tumor growth and metastasis in vivo. Pharmacological inhibition of GFPT1 and OGT leads to significant inhibition of cellular proliferation and colony formation in CRC cells. In summary, our results show that overexpression of FASN increases the expression of GFPT1 and OGT as well as the level of protein O-GlcNAcylation to promote progression of CRC; targeting the hexosamine biosynthesis pathway could be a therapeutic approach for this disease.
摘要：
脂肪酸合成已被广泛研究作为癌症的治疗靶标。包括结直肠癌（CRC）。脂肪酸合成酶(FASN),从头合成脂质的关键酶，在CRC中显著上调，和靶向这种酶的治疗方法目前正在多个临床试验中进行测试。然而,FASN的原癌作用背后的机制仍未完全了解.这里,第一次,我们显示FASN的过表达增加谷氨酰胺-果糖-6-磷酸转氨酶1（GFPT1）和O-连接的N-乙酰葡糖胺转移酶（OGT）的表达，参与己糖胺代谢的酶，以及体外和体内O-GlcNAcylation的水平。始终如一，FASN的表达与人CRC组织中GFPT1和OGT的表达显著相关。shRNA介导的GFPT1和OGT下调在体外抑制细胞增殖和蛋白O-GlcNAcylation水平，GFPT1的敲除导致体内肿瘤生长和转移的显着减少。GFPT1和OGT的药理学抑制导致CRC细胞中细胞增殖和集落形成的显著抑制。总之,我们的结果表明,FASN的过表达增加了GFPT1和OGT的表达以及蛋白O-GlcNAcylation的水平,从而促进CRC的进展;靶向己糖胺生物合成途径可能是该疾病的治疗方法.
