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Fatty Acid Synthase: an Emerging Target in Cancer

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Fatty Acid Synthase: an Emerging Target in Cancer molecules Review Fatty Acid Synthase: An Emerging Target in Cancer Chee Wai Fhu * and Azhar Ali * Cancer Science Institute Singapore, National University of Singapore, Singapore 117599, Singapore * Correspondence: [email protected] (C.W.F.); [email protected] (A.A.) Academic Editor: Pierluigi Plastina Received: 30 July 2020; Accepted: 26 August 2020; Published: 28 August 2020 Abstract: In recent years, lipid metabolism has garnered significant attention as it provides the necessary building blocks required to sustain tumor growth and serves as an alternative fuel source for ATP generation. Fatty acid synthase (FASN) functions as a central regulator of lipid metabolism and plays a critical role in the growth and survival of tumors with lipogenic phenotypes. Accumulating evidence has shown that it is capable of rewiring tumor cells for greater energy flexibility to attain their high energy requirements. This multi-enzyme protein is capable of modulating the function of subcellular organelles for optimal function under different conditions. Apart from lipid metabolism, FASN has functional roles in other cellular processes such as glycolysis and amino acid metabolism. These pivotal roles of FASN in lipid metabolism make it an attractive target in the clinic with several new inhibitors currently being tested in early clinical trials. This article aims to present the current evidence on the emergence of FASN as a target in human malignancies. Keywords: fatty acid synthase; cancer; lipid metabolism 1. Introduction Cancer hallmarks were introduced by Hanahan et al. in 2010 and these hallmarks encompass six basic tumor characteristics—which are self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis, unlimited replication potential, sustain angiogenesis, and evading apoptosis [1]. The whole paradigm was revised the following year to include metabolic reprogramming after a monumental effort had been spent on cancer metabolism studies [2]. Cancer metabolism was initially proposed by Otto Hendrich Warburg, termed Warburg’s effect, describing glucose consumption through glycolysis by cancer cells for ATP generation allowing tumor cell survival under aerobic condition [3]. In recent years, numerous studies have unraveled the dynamics of cancer metabolism and the concept of metabolic plasticity or metabolic rewiring of cancer cells was subsequently introduced. Apart from glucose utilization, cancer cells undergo various oncogenic mutations or adaptations to allow utilization of a more diverse range of nutrients including fatty acids (FAs) and amino acids for tumor survival, metastasis and disease progression. These findings have led to renewed interests to elucidate the diverse roles of lipid metabolism in cancer. This minireview aims to present current knowledge on fatty acid synthase FASN, its roles in cancer cell biology, metabolic reprogramming, and also the current challenges of FASN-targeted therapy. 2. FASN in Normal Physiology FASN is a large multi-enzyme complex and the monomeric protein size is ~270 kDa. It comprises six separate enzymatic grooves that work together to produce a 16-carbon chain saturated fatty acid (FA), palmitate, from acetyl-coenzyme A (CoA) and malonyl-CoA in the presence of Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) [4]. The FASN monomer (Figure1) possesses enzymatic activities which include beta-ketoacyl synthase (KS), acetyl/malonyl transacylase (AT/MT), beta-hydroxyacyl dehydratase (DH), enoyl reductase (ER), beta-ketoacyl reductase (KR), acyl carrier Molecules 2020, 25, 3935; doi:10.3390/molecules25173935 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 22 Molecules 2020, 25, 3935 2 of 22 enzymatic activities which include beta-ketoacyl synthase (KS), acetyl/malonyl transacylase (AT/MT), beta-hydroxyacyl dehydratase (DH), enoyl reductase (ER), beta-ketoacyl reductase (KR), proteinacyl carrier (ACP), protein and thioesterase (ACP), and (TE). thioesterase Although (TE). the FASN Although monomer the containsFASN monomer all the necessary contains enzymes all the needednecessary for enzymes palmitate needed synthesis, for palmitate the dimer synthesis, formation the is crucialdimer formation for its function. is crucial The for structure its function. of FASN The canstructure be further of FASN categorized can be further into three categorized major domains into three where major domain domains I contains where domain KS, AT I/ MTcontain andsDH, KS, domainAT/MT IIand contains DH, domain ER, KR andII contains ACP,and ER, domain KR and III ACP, contains and TE. domain About III a quartercontains length TE. About of the monomera quarter protein,length of located the monomer between protein, domains located I and II, between which lacks domains catalytic I and activity, II, which is called lacks the catalytic interdomain activity,/core is regioncalled the and interdomain/cor is identified to bee region crucial and for is dimer identified formation to be [crucial5]. for dimer formation [5]. Figure 1.1. FattyFatty acid acid synthase synthase (FASN) (FASN structure.) structure. (A )( RepresentsA) Represents the linearthe linear sequence sequence organization organization of FASN of monomer.FASN monomer. (B). Structural (B). Structural overview ofoverview FASN comprising of FASN twocomprising identical monomers,two identical each monomers, including seveneach catalyticincluding domains: seven catalytic beta-ketoacyl domains: synthase beta-ketoacyl (KS), acetyl synthase/malonyl (KS), transacylase acetyl/malonyl (AT/ MT),transacylase beta-hydroxyacyl (AT/MT), dehydratasebeta-hydroxyacyl (DH), dehydratase enoyl reductase (DH), (ER),enoyl beta-ketoacyl reductase (ER), reductase beta-ketoacyl (KR), reductase acyl carrier (KR), protein acyl (ACP),carrier andprotein thioesterase (ACP), and (TE). thioesterase (TE). FASN expressionexpression is is critical critical for for early early embryo embryo development, development, in which in FASNwhich knockoutFASN knockout (KO) embryos (KO) failembryos to survive fail to before survive implantation before implantation and the number and the of number FASN heterozygous of FASN heterozygous pups is 70% pups lower is than70% predictedlower than by predicted Mendelian by Inheritance, Mendelian whichInheritance, indicate which partial indicate haploid partial insuffi haploidciency [insufficiency6]. Furthermore, [6]. FASNFurther expressionmore, FASN is shown expression to participate is shown in to the participate proper development in the proper of development the fetal lung of and the the fetal normal lung functionalityand the normal of thefunctionality adult lung. of There the adult is ample lung. evidence There is demonstrating ample evidence that demonstrating the fetal lung that is capable the fetal of delung novo is capable FA synthesis of de and novo that FA FASN synthesis is required and forthat surfactant FASN is production required for of alveolarsurfactant epithelial production cells [7of]. Afteralveolar early epithelial development, cells [7] FASN. After remains early relativelydevelopment, quiescent FASN in mostremains tissues, relatively however quiescent the reason in most why thistissues is so, however still remains the reason elusive. why A plausiblethis is so still explanation remains iselusive. that non-actively A plausible proliferatingexplanation is tissues that non can- meetactively the proliferat FAs’ demanding tissues from the can diet meet tofulfil the FAs their’ demand physiological from FAthe requirements.diet to fulfil their Nonetheless, physiological a strong FA FASNrequirements. expression Nonetheless, has been reported a strong in FASN the lung, expression breast, liver,has been adipose reported and brain in the [8 ].lung, breast, liver, adiposeDeletion and brain of FASN [8]. in alveolar type II epithelial cells is found to disrupt surfactant lipid composition and exacerbateDeletion of injury FASN response in alveolar to bleomycin-induced type II epithelial fibrosis cells is [9 ].found The matureto disrupt mammary surfactant gland lipid is a uniquecomposition lipid and metabolizing exacerbate tissue injury where, response in resting-state,to bleomycin- itinduced does not fibrosis require [9] fatty. The acidmature synthesis mammary but stronglygland is inducesa unique FASN lipid during metabolizing pregnancy tissue and where lactation, in [resting10]. De-state, novo FAit does synthesis not require in the mammaryfatty acid glandsynthesis is responsible but strongly for induces producing FASN short during and medium pregnancy chain and FAs lactation in milk, [10] which. De account novo FA for synthesis ~15–40% ofin totalthe mammary FA content gland [11, 12is ].responsible Mammary for gland-specific producing short FASN and KO medium mice arechain shown FAs in to milk, suffer which from account growth reductionfor ~15–40% in of mammary total FA content epithelial [11,12] cells,. Mammary alteration ofgland the- FAsspecific profile FASN in milkKO mice from are lactating shown mothers,to suffer andfrom also growth improper reduction development in mammary of the functionalepithelial lactatingcells, alteration mammary of glandthe FAs [13 ].profile in milk from lactating mothers, and also improper development of the functional lactating mammary gland [13]. Molecules 2020, 25, 3935 3 of 22 FASN is considered as a housekeeping protein in the liver under normal physiological conditions where it controls the hepatic triglyceride mechanism. When carbohydrates are abundant, glucose are converted to
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