Pivotal Role of Fatty Acid Synthase in c-MYC Driven Hepatocarcinogenesis

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.

Therapeutic efficacy of FASN inhibition in preclinical models of HCC

“…[3] Using Fasn flox/flox conditional knockout mice, we have previously shown that sgPTEN/ c-MET and c-MYC mouse HCCs are addicted to FASN, whereas FASN is dispensable for β-cateninΔ90/c-METinduced hepatocarcinogenesis. [8][9][10] Consistently, our present study indicates that TVB3664 (in combination with cabozantinib) effectively suppresses the growth of FASN-dependent sgPTEN/c-MET and c-MYC murine HCCs. In contrast, it has no anti-tumor efficacy in FASN-independent β-cateninΔ90/c-MET hepatocarcinogenesis (Figure S38).…”

MYC Promotes LDHA Expression through MicroRNA-122-5p to Potentiate Glycolysis in Hepatocellular Carcinoma

“…Taken together, our study demonstrates a crucial role of MYC/miR-122-5p/LDHA in glycolysis, offering avenues for future therapy development in HCC. MYC, a well-characterized driving force in a vast network of organs including the liver, is a transcription factor that stimulates cellular transformation and tumor progression, and the significant role of MYC in hepatocarcinogenesis has been established unquestionably by the finding that MYC upregulation is efficient enough to initiate HCC development in mice [15]. In the present report, we not only substantiated that overexpression of MYC was correlated with dismal prognosis of HCC patients but also demonstrated that silencing of MYC hampered the glycolysis, migration, invasion, and growth of HCC cells.…”

Role of Lipogenesis Rewiring in Hepatocellular Carcinoma

“…67 Additional investigations have demonstrated that FASN is required for c-Myc-dependent hepatocarcinogenesis. 68 Furthermore, loss of FASN retards HCC development induced by overexpression of c-Met and loss of Pten (c-Met/sgPten) in mice. 69 Overall, these data indicate that FASN suppression is a promising therapeutic strategy for HCC treatment.…”