Abstract
Tumorigenesis involves metabolic reprogramming and abnormal lipid metabolism, which is manifested by increased endogenous fat mobilization, hypertriglyceridemia, and increased fatty acid synthesis. Fatty acid synthase (FASN) is a key enzyme for the de novo synthesis of fatty acids, and monoacylglycerol esterase (MGLL) is an important metabolic enzyme that converts triglycerides into free fatty acids. Both enzymes play an important role in lipid metabolism and are associated with tumor-related signaling pathways, the most common of which is the PI3K-AKT signaling pathway. They can also regulate the immune microenvironment, participate in epithelial-mesenchymal transition, and then regulate tumor invasion and metastasis. Current literature have shown that these two genes are abnormally expressed in many types of tumors and are highly correlated with tumor migration and invasion. This article introduces the structures and functions of FASN and MGLL, their relationship with abnormal lipid metabolism, and the mechanism of the regulation of tumor invasion and metastasis and reviews the research progress of the relationship of FASN and MGLL with tumor invasion and metastasis.
Similar content being viewed by others
References
Karlsson M, Reue K, Xia YR, Lusis AJ, Langin D, Tornqvist H, Holm C. Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene. Gene 2001; 272(1–2): 11–18
Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C. cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J Biol Chem 1997; 272(43): 27218–27223
Sun T, Liu Y, Liu L, Ma F. MicroRNA-544 attenuates diabetic renal injury via suppressing glomerulosclerosis and inflammation by targeting FASN. Gene 2020; 723: 143986
Wei X, Song H, Yin L, Rizzo MG, Sidhu R, Covey DF, Ory DS, Semenkovich CF. Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature 2016; 539(7628): 294–298
Huang LH, Chung HY, Su HM. Docosahexaenoic acid reduces sterol regulatory element binding protein-1 and fatty acid synthase expression and inhibits cell proliferation by inhibiting pAkt signaling in a human breast cancer MCF-7 cell line. BMC Cancer 2017; 17(1): 890
Li N, Bu X, Wu P, Wu P, Huang P. The “HER2-PI3K/Akt-FASN Axis” regulated malignant phenotype of colorectal cancer cells. Lipids 2012; 47(4): 403–411
Mo Y, Wu Y, Li X, Rao H, Tian X, Wu D, Qiu Z, Zheng G, Hu J. Osthole delays hepatocarcinogenesis in mice by suppressing AKT/FASN axis and ERK phosphorylation. Eur J Pharmacol 2020; 867: 172788
Chang L, Fang S, Chen Y, Yang Z, Yuan Y, Zhang J, Ye L, Gu W. Inhibition of FASN suppresses the malignant biological behavior of non-small cell lung cancer cells via deregulating glucose metabolism and AKT/ERK pathway. Lipids Health Dis 2019; 18(1): 118
Cao Z, Mulvihill MM, Mukhopadhyay P, Xu H, Erdélyi K, Hao E, Holovac E, Haskó G, Cravatt BF, Nomura DK. Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice. Gastroenterology 2013; 144(4): 808–817.e15
Jiang M, van der Stelt M. Activity-based protein profiling delivers selective drug candidate ABX-1431, a monoacylglycerol lipase inhibitor, to control lipid metabolism in neurological disorders. J Med Chem 2018; 61(20): 9059–9061
Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 2010; 140(1): 49–61
Sun H, Jiang L, Luo X, Jin W, He Q, An J, Lui K, Shi J, Rong R, Su W, Lucchesi C, Liu Y, Sheikh MS, Huang Y. Potential tumor-suppressive role of monoglyceride lipase in human colorectal cancer. Oncogene 2013; 32(2): 234–241
Rajasekaran D, Jariwala N, Mendoza RG, Robertson CL, Akiel MA, Dozmorov M, Fisher PB, Sarkar D. Staphylococcal nuclease and Tudor domain containing 1 (SND1 protein) promotes hepatocarcinogenesis by inhibiting monoglyceride lipase (MGLL). J Biol Chem 2016; 291(20): 10736–10746
Galli GG, Multhaupt HA, Carrara M, de Lichtenberg KH, Christensen IB, Linnemann D, Santoni-Rugiu E, Calogero RA, Lund AH. Prdm5 suppresses Apc(Min)-driven intestinal adenomas and regulates monoacylglycerol lipase expression. Oncogene 2014; 33(25): 3342–3350
Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr. Cellular fatty acid metabolism and cancer. Cell Metab 2013; 18(2): 153–161
Warburg O. On the origin of cancer cells. Science 1956; 123(3191): 309–314
Qiu H, Zhao X. Correlation between PI3K/AKT signal pathway and overexpression of fatty acid synthase in osteosarcoma. Chin J Gerontology (Zhongguo Lao Nian Xue Za Zhi) 2018; 9: 2113–2115 (in Chinese)
Jiang L, Fang X, Wang H, Li D, Wang X. Ovarian cancer-intrinsic fatty acid synthase prevents anti-tumor immunity by disrupting tumor-infiltrating dendritic cells. Front Immunol 2018; 9: 2927
Wang X, Du G, Wu Y, Zhang Y, Guo F, Liu W, Wu R. Association between different levels of lipid metabolismrelated enzymes and fatty acid synthase in Wilms’ tumor. Int J Oncol 2020; 56(2): 568–580
Li CF, Chuang IC, Liu TT, Chen KC, Chen YY, Fang FM, Li SH, Chen TJ, Yu SC, Lan J, Huang HY. Transcriptomic reappraisal identifies MGLL overexpression as an unfavorable prognosticator in primary gastrointestinal stromal tumors. Oncotarget 2016; 7(31): 49986–49997
Zhu W, Zhao Y, Zhou J, Wang X, Pan Q, Zhang N, Wang L, Wang M, Zhan D, Liu Z, He X, Ma D, Liu S, Wang L. Monoacylglycerol lipase promotes progression of hepatocellular carcinoma via NF-κB-mediated epithelial-mesenchymal transition. J Hematol Oncol 2016; 9(1): 127
Zhao M, Bu Y, Feng J, Zhang H, Chen Y, Yang G, Liu Z, Yuan H, Yuan Y, Liu L, Yun H, Wang J, Zhang X. SPIN1 triggers abnormal lipid metabolism and enhances tumor growth in liver cancer. Cancer Lett 2020; 470: 54–63
Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2(7): 489–501
Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, Fridlib M, Buckley D, Kemble G, Heuer TS. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine 2015; 2(8): 808–824
Yang X, Zhang D, Liu S, Li X, Hu W, Han C. KLF4 suppresses the migration of hepatocellular carcinoma by transcriptionally upregulating monoglyceride lipase. Am J Cancer Res 2018; 8(6): 1019–1029
Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, Meyerson M, Gabriel SB, Lander ES, Getz G. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014; 505(7484): 495–501
Jiang N, Dai Q, Su X, Fu J, Feng X, Peng J. Role of PI3K/AKT pathway in cancer: the framework of malignant behavior. Mol Biol Rep 2020; 47(6): 4587–4629
Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 2003; 17(3): 590–603
Danielsen SA, Eide PW, Nesbakken A, Guren T, Leithe E, Lothe RA. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim Biophys Acta 2015; 1855(1): 104–121
Xu F, Na L, Li Y, Chen L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci 2020; 10(1): 54
Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer 2020; 20(2): 74–88
Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14 (6): 818–829
Zielinska HA, Holly JMP, Bahl A, Perks CM. Inhibition of FASN and ERα signalling during hyperglycaemia-induced matrix-specific EMT promotes breast cancer cell invasion via a caveolin-1-dependent mechanism. Cancer Lett 2018; 419: 187–202
Xiang W, Shi R, Kang X, Zhang X, Chen P, Zhang L, Hou A, Wang R, Zhao Y, Zhao K, Liu Y, Ma Y, Luo H, Shang S, Zhang J, He F, Yu S, Gan L, Shi C, Li Y, Yang W, Liang H, Miao H. Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression. Nat Commun 2018; 9(1): 2574
Zielinska HA, Holly JMP, Bahl A, Perks CM. Inhibition of FASN and ERα signalling during hyperglycaemia-induced matrix-specific EMT promotes breast cancer cell invasion via a caveolin-1-dependent mechanism. Cancer Lett 2018; 419: 187–202
Wang J, Zhang X, Shi J, Cao P, Wan M, Zhang Q, Wang Y, Kridel SJ, Liu W, Xu J, Zhang Q, Sui G. Fatty acid synthase is a primary target of MiR-15a and MiR-16-1 in breast cancer. Oncotarget 2016; 7(48): 78566–78576
Yu Z, Xue H. AKT promotes tumorigenesis in mice through regulation FASN lipid metabolism. J Fujian Norm Univ (Natural Science Edition) 2019; 35(03): 58–64
Zhao J, Zhang X, Gao T, Wang S, Hou Y, Yuan P, Yang Y, Yang T, Xing J, Li J, Liu S. SIK2 enhances synthesis of fatty acid and cholesterol in ovarian cancer cells and tumor growth through PI3K/Akt signaling pathway. Cell Death Dis 2020; 11(1): 25
Cao Z, Xu Y, Guo F, Chen X, Ji J, Xu H, He J, Yu Y, Sun Y, Lu X, Wang F. FASN protein overexpression indicates poor biochemical recurrence-free survival in prostate cancer. Dis Markers 2020; 2020: 3904947
De Piano M, Manuelli V, Zadra G, Otte J, Edqvist PD, Pontén F, Nowinski S, Niaouris A, Grigoriadis A, Loda M, Van Hemelrijck M, Wells CM. Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases. Oncogene 2020; 39(18): 3666–3679
Zhang WL, Wang SS, Jiang YP, Liu Y, Yu XH, Wu JB, Wang K, Pang X, Liao P, Liang XH, Tang YL. Fatty acid synthase contributes to epithelial-mesenchymal transition and invasion of salivary adenoid cystic carcinoma through PRRX1/Wnt/α-catenin pathway. J Cell Mol Med 2020; 24(19): 11465–11476
Ghaeidamini Harouni M, Rahgozar S, Rahimi Babasheikhali S, Safavi A, Ghodousi ES. Fatty acid synthase, a novel poorprognostic factor for acute lymphoblastic leukemia which can be targeted by ginger extract. Sci Rep 2020; 10(1): 14072
Szeremeta J, Karlsson J, Alhouayek M, Fowler CJ. Low mRNA expression and activity of monoacylglycerol lipase in human SHSY5Y neuroblastoma cells. Prostaglandins Other Lipid Mediat 2019; 142: 59–67
Xiang W, Zhang D, Miao H. Monoacylglycerol lipase in macrophages suppresses melanoma by potentiating TLR4-Sirp α axis-mediated tumor phagocytosis. Abstracts of IUIS 2019 Beijing—17th International Congress of Immunology (II). The International Union of Immunological Societies (IUIS) and the Chinese Society for Immunology (CSI). 2019: 2
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81672637 and 81872164).
Author information
Authors and Affiliations
Corresponding author
Additional information
Compliance with ethics guidelines
Jingyue Zhang, Yawen Song, Qianqian Shi, and Li Fu declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol that require the approval of relevant institutional review board or ethics committee.
Rights and permissions
About this article
Cite this article
Zhang, J., Song, Y., Shi, Q. et al. Research progress on FASN and MGLL in the regulation of abnormal lipid metabolism and the relationship between tumor invasion and metastasis. Front. Med. 15, 649–656 (2021). https://doi.org/10.1007/s11684-021-0830-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11684-021-0830-0