Abstract
Hepatocellular carcinoma (HCC) is a deadly form of liver malignancy with limited treatment options. Amplification and/or overexpression of c-MYC is one of the most frequent genetic events in human HCC. The mammalian target of Rapamycin Complex 1 (mTORC1) is a major functional axis regulating various aspects of cellular growth and metabolism. Recently, we demonstrated that mTORC1 is necessary for c-Myc driven hepatocarcinogenesis as well as for HCC cell growth in vitro. Among the pivotal downstream effectors of mTORC1, upregulation of Fatty Acid Synthase (FASN) and its mediated de novo lipogenesis is a hallmark of human HCC. Here, we investigated the importance of FASN on c-Myc-dependent hepatocarcinogenesis using in vitro and in vivo approaches. In mouse and human HCC cells, we found that FASN suppression by either gene silencing or soluble inhibitors more effectively suppressed proliferation and induced apoptosis in the presence of high c-MYC expression. In c-Myc/Myeloid cell leukemia 1 (MCL1) mouse liver tumor lesions, FASN expression was markedly upregulated. Most importantly, genetic ablation of Fasn profoundly delayed (without abolishing) c-Myc/MCL1 induced HCC formation. Liver tumors developing in c-Myc/MCL1 mice depleted of Fasn showed a reduction in proliferation and an increase in apoptosis when compared with corresponding lesions from c-Myc/MCL1 mice with an intact Fasn gene. In human HCC samples, a significant correlation between the levels of c-MYC transcriptional activity and the expression of FASN mRNA was detected. Altogether, our study indicates that FASN is an important effector downstream of mTORC1 in c-MYC induced HCC. Targeting FASN may be helpful for the treatment of human HCC, at least in the tumor subset displaying c-MYC amplification or activation.
Highlights
Hepatocellular carcinoma (HCC) is the most frequent primary malignancy of the liver and the fourth most common cause of cancer-related death worldwide [1]
Fatty Acid Synthase (FASN) Inactivation is Detrimental for the Growth of c-MYC HCC Cell Lines 2.1
FASN Inactivation Is Detrimental for the Growth of c-MYC HCC Cell Lines Recently, it has been demonstrated that c-MYC induced growth is severely hindered by the iFlinAvheSiriFbNnAicthaiiSoinnbNncRitetheiiornoicfsecntentphhlotrilelssofyc,tpimehnirsteTosvcOh,mietanRrsTsaosCOm,.b1nFeRe/aeoSlCymnrR1Ewted/hSlBeeyiRPsmaEw1psoBseupnPeraass1ptstsrhosepaewsdatesetas,wdheytwhdht[eeha3wtay2hHht]e[.Cecr3tH-C2FhM]eA3e.rY-rS4eHCFN, aAewnirsSnedeuNd,peHuwpsvcCueraeeplCdeusp4vsagir-ato4erelnosudmswaaitotofthefnhuedescaietstsffshpHeseteechcCtvseispCfeigtercherccoeleciyfiowlglcnhrtltohicirnnowioebdnstfueth,rctrwii-eoboMdfhuncYitbc-ioCoMyhfntYhoCef werelivperrevciaonucselrycdeellrsivinedviftrroom
Summary
Hepatocellular carcinoma (HCC) is the most frequent primary malignancy of the liver and the fourth most common cause of cancer-related death worldwide [1]. Increased levels of FASN and related de novo lipogenesis have been observed in multiple cancer types, including tumors of the breast, gastrointestinal tract, prostate, bladder, ovary, lung, oral cavity, and head and neck [26,27]. Subsequent experiments revealed that silencing of FASN decreases HCC cell growth and increases apoptosis in vitro, and ablation of FASN completely suppresses AKT and AKT/c-Met driven HCC formation in mice [25,30]. These studies provide the evidence, for the first time, that FASN and its mediated lipogenesis are required for HCC growth in vivo [29]. RTeOcRenCt1ly,awxiesfoisunndeetdheadt anfoirntca-cMt ymcT-dOrRivCe1n ahxeispiastonceaerdceindofgoernce-sMisyc[3-d1r].iven Furthheeprmatorcea,rciitnhoagsenbeseins [r3e1v]e. aFluedrththearmt co-rMe,YitChacosobpeernartesvewaliethd SthRaEtBcP-M1 YtoCicnodoupceeralitpeos gweinthesSisRaEnBdP1 to prominodtuecenleioppolgaesntiecsislivanerd pgrroomwothte n[3e2o]p. laHstoicwleiver,grtohwe thsp[3e2ci]f.icHocwonetvreibr,utthioenspoecfifiFcAcSoNntriabluotnigon of hepaFtAoScaNrcainloonggenheespisationcdaurceindobgyentheesics-iMndYuCceodncboyprthoteecin-MhYasCnoenvecor pbreoetneinvheasstingeavteedr tboeednatien.vestigated toIndtahte.present study, we determined the functional relevance and the possible therapeutic role of FASNIonnthc-eMpYreCsednetpsetundye,nwt heedpeatetormcairnceindotgheenfeusnisctbioyneaml rpelloeyvianngceinavnidtrtohaenpdosinsibvlievothaeprapproeuactihcerso.le of FASN on c-MYC dependent hepatocarcinogenesis by employing in vitro and in vivo approaches
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