Dell Pediatric Research Institute, Dell Medical School and Department of Nutritional Sciences, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA.
Dell Pediatric Research Institute, Dell Medical School and Department of Nutritional Sciences, The University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA.
Prog Lipid Res. 2023 Nov;92:101242. doi: 10.1016/j.plipres.2023.101242. Epub 2023 Aug 18.
Dysregulation of fatty acid metabolism and de novo lipogenesis is a key driver of several cancer types through highly unsaturated fatty acid (HUFA) signaling precursors such as arachidonic acid. The human chromosome 11q13 locus has long been established as the most frequently amplified in a variety of human cancers. The fatty acid desaturase genes (FADS1, FADS2 and FADS3) responsible for HUFA biosynthesis localize to the 11q12-13.1 region. FADS2 activity is promiscuous, catalyzing biosynthesis of several unsaturated fatty acids by Δ6, Δ8, and Δ4 desaturation. Our main aim here is to review known and putative consequences of FADS2 dysregulation due to effects on the 11q13 locus potentially driving various cancer types. FADS2 silencing causes synthesis of sciadonic acid (5Z,11Z,14Z-20:3) in MCF7 cells and breast cancer in vivo. 5Z,11Z,14Z-20:3 is structurally identical to arachidonic acid (5Z,8Z,11Z,14Z-20:4) except it lacks the internal Δ8 double bond required for prostaglandin and leukotriene synthesis, among other eicosanoids. Palmitic acid has substrate specificity for both SCD and FADS2. Melanoma, prostate, liver and lung cancer cells insensitive to SCD inhibition show increased FADS2 activity and sapienic acid biosynthesis. Elevated serum mead acid levels found in hepatocellular carcinoma patients suggest an unsatisfied demand for arachidonic acid. FADS2 circular RNAs are at high levels in colorectal and lung cancer tissues. FADS2 circular RNAs are associated with shorter overall survival in colorectal cancer patients. The evidence thusfar supports an effort for future research on the role of FADS2 as a tumor suppressor in a range of neoplastic disorders.
脂肪酸代谢和从头合成的失调是几种癌症类型的关键驱动因素，其通过高度不饱和脂肪酸 (HUFA) 信号前体如花生四烯酸来实现。人类 11 号染色体 q13 位点长期以来一直被确定为多种人类癌症中最常扩增的区域。负责 HUFA 生物合成的脂肪酸去饱和酶基因 (FADS1、FADS2 和 FADS3) 位于 11q12-13.1 区域。FADS2 活性具有混杂性，通过 Δ6、Δ8 和 Δ4 去饱和作用催化几种不饱和脂肪酸的生物合成。我们的主要目的是综述由于 11q13 位点效应导致 FADS2 失调的已知和推测后果，这些后果可能会驱动各种癌症类型。FADS2 沉默导致 MCF7 细胞和体内乳腺癌中合成山嵛酸 (5Z,11Z,14Z-20:3)。5Z,11Z,14Z-20:3 在结构上与花生四烯酸 (5Z,8Z,11Z,14Z-20:4) 相同，只是缺少用于前列腺素和白三烯合成的内部 Δ8 双键，以及其他类二十烷酸。棕榈酸对 SCD 和 FADS2 都具有底物特异性。对 SCD 抑制不敏感的黑色素瘤、前列腺癌、肝癌和肺癌细胞显示出 FADS2 活性和芝麻酸生物合成增加。在肝细胞癌患者中发现的血清中马尿酸水平升高表明对花生四烯酸的需求未得到满足。FADS2 环状 RNA 在结直肠癌和肺癌组织中水平较高。FADS2 环状 RNA 与结直肠癌患者的总生存期缩短有关。迄今为止的证据支持对 FADS2 在一系列肿瘤性疾病中作为肿瘤抑制因子的作用进行未来研究。
