Interplay Between Fatty Acids, Stearoyl-Co-A Desaturase, Mechanistic Target of Rapamycin, and Yes-Associated Protein/Transcriptional Coactivator With PDZ-Binding Motif in Promoting Hepatocellular Carcinoma

Abstract

Nonalcoholic fatty liver disease has reached pandemic proportions with one of its most consequential complications being hepatocellular carcinoma (HCC). Nonalcoholic fatty liver disease-related HCC is becoming the leading indication for liver transplantation in the United States. Given the scarcity of available organs, early detection and prevention remain key in prevention and management of the disease. Over the years, the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) pathway emerged as a key signal transduction pathway in the pathogenesis of HCC. In this review, we explore the interplay between the YAP/TAZ pathway as a point of convergence in HCC pathogenesis. We review the evidence of how lipid reprogramming and key lipid pathways, saturated and monounsaturated fatty acids (through the rate-limiting enzyme stearoyl Co-A desaturase), the mevalonic acid pathway (the role of statins), and mechanistic target of rapamycin all play critical roles in intricate and complex networks that tightly regulate the YAP/TAZ pro-oncogenic pathway. Nonalcoholic fatty liver disease has reached pandemic proportions with one of its most consequential complications being hepatocellular carcinoma (HCC). Nonalcoholic fatty liver disease-related HCC is becoming the leading indication for liver transplantation in the United States. Given the scarcity of available organs, early detection and prevention remain key in prevention and management of the disease. Over the years, the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) pathway emerged as a key signal transduction pathway in the pathogenesis of HCC. In this review, we explore the interplay between the YAP/TAZ pathway as a point of convergence in HCC pathogenesis. We review the evidence of how lipid reprogramming and key lipid pathways, saturated and monounsaturated fatty acids (through the rate-limiting enzyme stearoyl Co-A desaturase), the mevalonic acid pathway (the role of statins), and mechanistic target of rapamycin all play critical roles in intricate and complex networks that tightly regulate the YAP/TAZ pro-oncogenic pathway. Primary liver cancer is the second leading cause of cancer death worldwide.1Sung H. Ferlay J. Siegel R.L. et al.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (24505) Google Scholar Hepatocellular carcinoma (HCC), which comprises 90% of the cases, commonly presents in patients with hepatic fibrosis associated with chronic hepatitis B virus or hepatitis C virus, excessive alcohol consumption, or the metabolic syndrome (MetS). As described below, the genetic landscape of HCC is complex and includes mutations in the Wnt/β-catenin (CTNNB1) pathway, chromatin remodeling, telomere maintenance, and inactivation of p53. In the USA, liver cancer incidence rates have more than tripled since 1980, while the cancer-associated death rates have more than doubled during this time. In parallel, nonalcoholic fatty liver disease (NAFLD), a common condition in patients with obesity and type 2 diabetes, has reached pandemic proportions and continues to rise.2Estes C. Razavi H. Loomba R. et al.Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.Hepatology. 2018; 67: 123-133Crossref PubMed Scopus (960) Google Scholar In the era of direct-acting antiviral therapy for hepatitis C virus and improved hepatitis B virus treatment, NAFLD-HCC is predicted to become the leading indication for liver transplantation.3Younossi Z.M. Stepanova M. Ong J. et al.Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States.Clin Gastroenterol Hepatol. 2021; 19: 580-589.e5Abstract Full Text Full Text PDF PubMed Google Scholar As liver transplantation remains a scarce resource with recent evidence suggesting that HCCs are transplanted less often following changes in United States Organ Procurement Network policy,4Kwong A.J. Ghaziani T.T. Mehta N. Decreased urgency among liver transplantation candidates with hepatocellular carcinoma in the United States.Liver Transpl. 2022; 28: 725-727Crossref PubMed Scopus (2) Google Scholar understanding its underlying mechanisms is of upmost importance to develop and implement chemoprevention and early detection programs, as well as tailor treatment approaches. NAFLD and HCC are complex diseases that result from genetic and environmental interactions.5Eslam M. Valenti L. Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact.J Hepatol. 2018; 68: 268-279Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar Many clinical potentially modifiable risk factors have been associated with NAFLD-HCC development, including features of the MetS, as defined by the clustering of type 2 diabetes, hypertension, dyslipidemia, and obesity, where each condition plays an additive or synergistic role in the pathogenesis of NAFLD-HCC.6Simon T.G. King L.Y. Chong D.Q. et al.Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies.Hepatology. 2018; 67: 1797-1806Crossref PubMed Scopus (68) Google Scholar,7Kanwal F. Kramer J.R. Mapakshi S. et al.Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.Gastroenterology. 2018; 155: 1828-1837.e2Abstract Full Text Full Text PDF PubMed Google Scholar Although statins are commonly prescribed for the treatment of dyslipidemia and the MetS, their use has been shown to be protective in all etiologies of HCC,8Singh S. Singh P.P. Singh A.G. et al.Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis.Gastroenterology. 2013; 144: 323-332Abstract Full Text Full Text PDF PubMed Google Scholar,9Simon T.G. Duberg A.S. 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Butler R.S. et al.Chemopreventive effect of statin on hepatocellular carcinoma in patients with nonalcoholic steatohepatitis cirrhosis.Am J Gastroenterol. 2021; 116: 2258-2269Crossref PubMed Scopus (7) Google Scholar The mechanisms involved in NAFLD-related HCC pathogenesis are therefore of major fundamental and translational importance but remain incompletely understood. In a large veteran population, the estimated incidence of HCC in the patients with NAFLD is 0.21/1000 person-years (PY), with the highest incidence occurring in the subpopulation of patients with cirrhosis (10.6/1000 PY).7Kanwal F. Kramer J.R. Mapakshi S. et al.Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease.Gastroenterology. 2018; 155: 1828-1837.e2Abstract Full Text Full Text PDF PubMed Google Scholar Simon et al6Simon T.G. King L.Y. Chong D.Q. et al.Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies.Hepatology. 2018; 67: 1797-1806Crossref PubMed Scopus (68) Google Scholar demonstrated similar findings in a European population-based cohort of biopsy-proven NAFLD and NASH, where HCC occurred at an incidence of 6.2/1000 PY for patients with underlying cirrhosis (95% confidence interval 4.2–8.8/1000 PY). The incidence of HCC was lower for patients with biopsy-proven simple steatosis (n = 5939) at 0.8/1000 PY and NASH without fibrosis (n = 1050) at 1.2/1000 PY.6Simon T.G. King L.Y. Chong D.Q. et al.Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies.Hepatology. 2018; 67: 1797-1806Crossref PubMed Scopus (68) Google Scholar The differences in incidence and disease progression likely reflect the heterogeneity in the NAFLD population, potentially nonmodifiable genetic differences, and their gene-environment interactions. There is evidence from previous genome-wide association studies demonstrating a predominance of NAFLD in Hispanic patients, followed by Caucasians and African Americans,12Romeo S. Kozlitina J. Xing C. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2215) Google Scholar which have been further substantiated in the HCC population.13Trepo E. Caruso S. 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El-Serag H.B. Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol. 2021; 18: 223-238Crossref PubMed Scopus (437) Google Scholar and health-care-associated costs17Allen A.M. Van Houten H.K. Sangaralingham L.R. et al.Healthcare cost and utilization in nonalcoholic fatty liver disease: real-world data from a large U.S. Claims Database.Hepatology. 2018; 68: 2230-2238Crossref PubMed Scopus (70) Google Scholar prompt the need for further research in this population, as outlined by recent professional society recommendations.18Kanwal F. Shubrook J.H. Younossi Z. et al.Preparing for the NASH epidemic: a call to action.Metabolism. 2021; 122: 154822Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Heritability of NAFLD and NASH has been suggested based on early observations of the clustering of disease in families and twins.19Schwimmer J.B. Celedon M.A. Lavine J.E. et al.Heritability of nonalcoholic fatty liver disease.Gastroenterology. 2009; 136: 1585-1592Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar,20Loomba R. Schork N. Chen C.H. et al.Heritability of hepatic fibrosis and steatosis based on a prospective twin study.Gastroenterology. 2015; 149: 1784-1793Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar In NAFLD-related HCC, teasing out inherited genetic contributions from chronic fibrosis/cirrhosis vs NAFLD-specific causes using genome-wide association studies remains a challenge and is still being investigated. Independent of its genetic predisposing factors, HCC often results from an accumulation of somatic mutations that lead to tumor initiation and progression. Studies have demonstrated that each HCC has about 40–60 somatic mutations, several of which converge on key molecular pathways.21Llovet J.M. Zucman-Rossi J. Pikarsky E. et al.Hepatocellular carcinoma.Nat Rev Dis Primers. 2016; 2: 16018Crossref PubMed Google Scholar Many mutations affect telomere maintenance (telomere reverse transcriptase activation); Wnt activation (mutation in CTNNB1 which encodes β-catenin, APC, and AXIN1); the tumor suppressor p53 gene (TP53); chromatin remodeling (including in the adenine-thymine-rich interactions-rich interaction domain 1A or ARID1A); activation of the PI3K/mechanistic target of rapamycin (mTORC1); and activation of receptor tyrosine kinases.21Llovet J.M. Zucman-Rossi J. Pikarsky E. et al.Hepatocellular carcinoma.Nat Rev Dis Primers. 2016; 2: 16018Crossref PubMed Google Scholar, 22Llovet J.M. Kelley R.K. Villanueva A. et al.Hepatocellular carcinoma.Nat Rev Dis Primers. 2021; 7: 6Crossref PubMed Scopus (1262) Google Scholar, 23Chiang D.Y. Villanueva A. 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Arretxe E. et al.The altered serum lipidome and its diagnostic potential for non-alcoholic fatty liver (NAFL)-associated hepatocellular carcinoma.EBioMedicine. 2021; 73103661Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar The authors propose that the lower MUFA and polyunsaturated fatty acids pool may be related to an increase in the uptake of these lipid species by the HCCs from the serum to sustain their growth and proliferation. Consistent with these findings, Muir et al,47Muir K. Hazim A. He Y. et al.Proteomic and lipidomic signatures of lipid metabolism in NASH-associated hepatocellular carcinoma.Cancer Res. 2013; 73: 4722-4731Crossref PubMed Scopus (110) Google Scholar identified that stearoyl-Co-A desaturase (SCD), the rate-limiting enzyme in the conversion of saturated fatty acids (SFAs) to MUFAs, which is preferentially found on the endoplasmic reticulum, was upregulated in human NAFLD-related HCC samples and Pten-null NASH-HCC murine models. While unsaturated fatty acids are required for cellular proliferation and membrane biogenesis, fatty acids also play important signaling functions that remain much less understood. As indicated above, SCD plays a critical role in regulating the ratio of unsaturated fatty acids/SFAs. MUFAs represent the precursors of the main components of cellular membranes and are crucially important in the pathogenesis of the MetS, NAFLD, NASH, and HCC pathogenesis.48Chiappini F. Coilly A. Kadar H. et al.Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients.Sci Rep. 2017; 746658Crossref Scopus (110) Google Scholar, 49Walle P. Takkunen M. Mannisto V. et al.Fatty acid metabolism is altered in non-alcoholic steatohepatitis independent of obesity.Metabolism. 2016; 65: 655-666Abstract Full Text Full Text PDF PubMed Google Scholar, 50Lai K.K.Y. Kweon S.M. Chi F. et al.Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6.Gastroenterology. 2017; 152: 1477-1491Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar This is supported by clinical studies demonstrating worse overall survival of patients with HCCs who demonstrate a high SCD expression, compared to HCCs with low SCD expression. Consistent with SCD playing a critical role in HCC tumor growth, Bansal et al51Bansal S. Berk M. Alkhouri N. et al.Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma.J Surg Res. 2014; 186: 29-38Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar demonstrated the inverse relationship between SCD gene expression patterns and HCC tumor differentiation. Similarly, the role of SCD in HCC is further supported by an elevated serum saturated to unsaturated phosphatidylcholine (16:0/16:1) level in patients with cirrhosis and HCC.50Lai K.K.Y. Kweon S.M. Chi F. et al.Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6.Gastroenterology. 2017; 152: 1477-1491Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar,52Cotte A.K. Cottet V. Aires V. et al.Phospholipid profiles and hepatocellular carcinoma risk and prognosis in cirrhotic patients.Oncotarget. 2019; 10: 2161-2172Crossref PubMed Scopus (4) Google Scholar Mechanistic studies of SCD and MUFAs in chronic liver disease point to selective effects of SCD on different resident liver cell types including M1 macrophage, hepatic stellate cells, and hepatocytes.53Kikuchi K. Tsukamoto H. Stearoyl-CoA desaturase and tumorigenesis.Chem Biol Interact. 2020; 316: 108917Crossref PubMed Scopus (0) Google Scholar These data suggest that the TME, supported by these other cell types, may play an integral role in HCC growth and aggressiveness. However, detailed human cell-type studies are lacking and have only recently been able to be identified with the advent of single-cell and single-nucleus RNA sequencing.54Slyper M. Porter C.B.M. Ashenberg O. et al.A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors.Nat Med. 2020; 26: 792-802Crossref PubMed Scopus (1) Google Scholar, 55Alvarez M. Benhammou J.N. Darci-Maher N. et al.Human liver single nucleus and single cell RNA sequencing identify a hepatocellular carcinoma-associated cell-type affecting survival.Genome Med. 2022; 14: 50Crossref PubMed Scopus (2) Google Scholar As shown in Figure 1, SCD expression is regulated at multiple levels,56Benhammou J.N. Ko A. Alvarez M. et al.Novel lipid long intervening noncoding RNA, oligodendrocyte maturation-associated long intergenic noncoding RNA, regulates the liver steatosis gene stearoyl-coenzyme A desaturase as an enhancer RNA.Hepatol Commun. 2019; 3: 1356-1372Crossref PubMed Google Scholar including by the sterol regulatory element-binding protein 1 (SREBP1), the master transcription regulator of lipid biosynthesis, which has higher expression in HCC through mammalian target of rapamycin (mTOR) signaling. mTOR Functions as a catalytic subunit in 2 distinct multiprotein complexes, the mTORC1, characterized by the subunit Raptor (regulatory-associated protein of mTORC1), and mTORC2, characterized by the subunit Rictor (Raptor-independent companion of mTORC2). The heterodimer of the tumor suppressor TSC1 and TSC2 represses mTORC1 activity by acting as the GTPase-activating protein for Rheb, a potent activator of mTORC1 in its guanosine triphosphate-bound state (Figure 1). Using an interactive open-access database (www.proteinatlas.org/pathology), we found that higher expression of Rheb is significantly associated with poor survival in HCC cases (Figure 2A). In the presence of amino acids, activated Akt and/or an extracellular signal-regulated kinasesK/p90RSK phosphorylate and uncouple TSC1/TSC2 from Rheb, leading to Rheb-GTP accumulation and mTORC1 activation at lysosomal membranes, which then promotes cell growth.57Porstmann T. Santos C.R. Griffiths B. et al.SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.Cell Metab. 2008; 8: 224-236Abstract Full Text Full Text PDF PubMed Scopus (950) Google Scholar Ragulator complex proteins LAMTOR 1, 3, and 5, which are involved in amino acid sensing and mTORC1 activation, are also significantly associated with unfavorable prognosis (survival) in HCC (Figure 2B–D). The association of Rheb and LAMTORS 1, 3, and 5 with unfavorable prognosis emphasizes the importance of mTORC1 function in HCC development. In turn, mTORC1 increases lipogenesis through regulation of SREBP1 at several levels, including trafficking, processing, and transcription58Han J. Wang Y. mTORC1 signaling in hepatic lipid metabolism.Protein Cell. 2018; 9: 145-151Crossref PubMed Scopus (73) Google Scholar that culminate in its nuclear localization and transcriptional activation. In turn, nuclear SREBP1 induces the expression of lipogenesis genes, including SCD.Figure 2Kaplan-Meier plots for gene expression of the signaling network in HCC. Images were reproduced from the Human Protein Atlas (version 17) available from www.proteinatlas.org.59Uhlén M. Fagerberg L. Hallström B.M. et al.Proteomics. Tissue-based map of the human proteome.Science. 2015; 347: 1260419Crossref PubMed Google Scholar Transcriptomics data were available from 365 patients in total with 119 female and 246 male patients. A majority of patients (n = 235) were still alive at the time of data collection. The stage distribution was (i) 170 patients, stage (ii) 84 patients, stage (iii) 83 patients, stage (iv) 4 patients, and 24 patients with missing data information. The links to the specific genes shown are as follows:Show full caption(A) Rheb: https://www.proteinatlas.org/ENSG00000106615-RHEB/pathology/liver+cancer/(B) LAMTOR1: https://www.proteinatlas.org/ENSG00000149357-LAMTOR1/pathology/liver+cancer(C) LAMTOR3: https://www.proteinatlas.org/ENSG00000109270-LAMTOR3/pathology/liver+cancer(D) LAMBOR5: https://www.proteinatlas.org/ENSG00000134248-LAMTOR5/pathology/liver+cancer(E) SAV1: https://www.proteinatlas.org/ENSG00000151748-SAV1/pathology/liver+cancer(F) BIRC5: https://www.proteinatlas.org/ENSG00000089685-BIRC5/pathology/liver+cancer(G) TEAD2: https://www.proteinatlas.org/ENSG00000074219-TEAD2/pathology/liver+cancer(H) Mob4: https://www.proteinatlas.org/ENSG00000115540-MOB4/pathology/liver+cancer.View Large