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Open AccessReview

Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

by 1,†, 2,3,†, 1,* and 2,3,4,*
1
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
2
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
3
Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China
4
State Key Laboratory of Digestive Disease and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Samy L. Habib
Cancers 2016, 8(8), 76; https://doi.org/10.3390/cancers8080076
Received: 20 June 2016 / Revised: 1 August 2016 / Accepted: 15 August 2016 / Published: 20 August 2016

Abstract

Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.
Keywords: non-alcoholic fatty liver disease; hepatocellular carcinoma; Wnt; β-catenin; epigenetics; DNA methylation; histone modification; microRNA; HDAC8 non-alcoholic fatty liver disease; hepatocellular carcinoma; Wnt; β-catenin; epigenetics; DNA methylation; histone modification; microRNA; HDAC8

1. Epigenetics in NAFLD-HCC

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and the second leading cause of cancer-related mortality [1]. In the past decade, the incidence of HCC has been increasing in almost all countries. Although many risk factors of HCC are well documented, such as infection of hepatitis B virus (HBV) and hepatitis C virus (HCV), obesity and type 2 diabetes, the latter two factors have emerged as the major factors responsible for the recent increase of HCC incidence [2]. Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress further to end-stage liver diseases like cirrhosis and HCC [3]. NAFLD is closely associated with central obesity, over-nutrition, insulin resistance and other features of metabolic syndrome [4]. It seems likely that the growing epidemic of NAFLD-associated HCC can be attributed to westernized and over-nutrition lifestyles, particularly in Asian populations [5,6].
Epigenetics refers to chromatin modifications exclusive of alterations in nucleotide sequences. It mainly includes DNA methylation, histone modifications and microRNAs (miRNAs), which can, respectively, activate or silence gene transcription (or act post-transcriptionally in the case of miRNAs), leading to diverse functional effects. Indeed, complex roles have been reported for a variety of chromatin modifiers, including but not limited to DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs) and histone deacetylases (HDACs) [7]. It is now evident that epigenetics plays crucial roles in many human diseases particularly cancer [8], especially in HCCs [9,10,11,12,13,14]. However, the roles of epigenetic regulation in metabolic abnormalities still remain elusive [15].
Although genomic study of NAFLD has been an established area of research for some time, the relevance of epigenomic factors such as DNA methylation in NAFLD development has only become apparent in recent years [16]. For instance, Pogribny and colleagues identified that mice fed with lipogenic methyl-deficient diet suffered from liver injuries resembling human NASH, in which livers displayed altered expression of the DNA methyltransferases DNMT1 and DNMT3A, less cytosine methylation at genomic and repetitive sequences, and abnormal histone modifications [17]. Concordantly, other studies demonstrated that many NAFLD candidate genes are aberrantly methylated in obesity or type 2 diabetes, and displayed altered expression in HCCs [18,19]. In addition, Relton et al. demonstrated some genes that were significantly correlated with variation in body size displayed hypermethylation in gene promoters or reduced gene expression in HCC [20]. Among them, ALOX25 and IRF5 are of interest because they are consistently hypermethylated in obesity and HCC samples [18,19].
Recently, altered expression and activities of certain HDACs/HATs have been linked to deregulated histone acetylation and gene expression in NAFLD, leading to abnormal metabolism and cellular transformation. Several HDACs have been shown to be critical modulators in the pathophysiology of NAFLD. Among them, HDAC3 is the most well-studied epigenetic modifier that can govern both circadian metabolic activity and hepatic lipid homeostasis [21,22,23]. Additionally, HDAC3 is frequently up-regulated in liver cancers, which make it a critical linkage between NAFLD and HCC [15].
MiRNAs have emerged as key regulators of metabolism [24]. The metabolic miRNAs, including miR-33, miR-103, miR-107 and miR-143, play pivotal roles in controlling the metabolism and homeostasis of insulin, glucose, cholesterol and lipid in vivo [25,26,27]. It has become clear that alterations in the expression of miRNAs contribute to the pathogenesis of most human cancers [28,29,30]. A number of differentially-expressed miRNAs that function in hepatic cholesterol and fatty acid homeostasis have been shown to contribute to the pathogenesis of HCC in NAFLD [15].

2. Wnt/β-Catenin Signaling and Epigenetics

The canonical or Wnt/β-catenin pathway is the best characterized Wnt pathway. Up to half of HCC patients have activation of Wnt/β-catenin signaling pathway [31,32,33]. When Wnt signaling is suppressed, generally due to a combination of lack of Wnt ligands and a prevalence of Wnt antagonists, β-catenin is sequentially phosphorylated by CK1 and GSK3β [34]. Upon phosphorylation, β-catenin is recognized by β-transducin repeat-containing protein for ubiquitination and degradation [35]. Alternatively, activation of Wnt signaling via interaction of a Wnt ligand with the Frizzle/LRP co-receptor complex halts the β-catenin degradation process, resulting in β-catenin accumulation in the cytoplasm and subsequent translocation into the nucleus, which then partners with the nuclear transcription complex TCF/LEF to increase the expression of a range of downstream targets to promote liver cancer formation [36].
An increasing body of evidence indicates that regulators controlling Wnt/β-catenin signaling are frequently dysregulated in human cancers owing to genetic and epigenetic defects [37]. Mutations of pathway components including APC, AXIN1/2 and CTNNB1 (encoding β-catenin) are common in HCC. These tumor-causative mutations lead to inappropriate stabilization of β-catenin, which persistently activates target genes associated with cell proliferation and transformation, such as cell cycle drivers cyclin D1 (CCND1) and c-Myc [38,39]. Alternatively, functional loss of Wnt inhibitors by epigenetic silencing, through either DNA methylation or histone modification, has also been recently reported to contribute to the aberrant activation of Wnt/β-catenin signaling in tumors. Different classes of epigenetically deregulated Wnt antagonists include extracellular Wnt inhibitors (SFRP1-5, WIF1 and DKK1-3), cytosolic Wnt inhibitors (DACT1-3, AXIN2, APC), nuclear factors (SOX7, 17), Wnt non-transforming ligands (Wnt5A, 7A, 9A), and epithelial adhesion molecules (CDH1) [40]. The growing list of epigenetically silenced Wnt antagonists in various human cancers suggests an important role for epigenetic regulation of Wnt/β-catenin pathway in tumor initiation and progression. For examples, TCF/β-catenin binding to Wnt responsive element (WRE) can lead to histone acetylation in a CBP-dependent manner over a significant genomic distance (30 kb), suggesting that local TCF/β-catenin recruitment results in widespread chromatin modifications. In addition, histone H3 lysine 4 trimethylation (H3K4me3), a typical indicator of active gene transcription, was detected at the WRE of c-Myc gene, which is a known Wnt target gene in cancer cells [41].

3. Epigenetic Regulation of Wnt/β-Catenin Signaling in NAFLD-HCC

Activation of Wnt/β-catenin signaling can drive the expression of specific oncogenes in various human cancers. CTNNB1, APC and AXIN gene mutations are classic defects that trigger chronic Wnt signaling in cancers [42]. However, the frequencies of these mutations are very low in certain malignancies such as HCC, wherein CTNNB1 mutation rate was 12%–16%, AXIN mutation rate was 8%–15%, and no mutation of APC was reported [43,44]. This evidence implicates that epigenetic deregulation may account for the abnormal Wnt/β-catenin activity in these models [45]. Indeed, in 100 human frozen liver biopsies of mild and advanced NAFLD patients, 69,247 differentially methylated CpG sites (between mild and advanced disease) with correlated expression changes were identified. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, and genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and underexpressed. These findings support that epigenetic dysregulation is associated with NAFLD progression and HCC initiation [46].

3.1. DNA Methylation

The secreted frizzled-related protein (SFRP) family is a class of extracellular Wnt inhibitors that act at cell membrane to prevent Wnt-mediated induction of β-catenin [47]. Promoter methylation-dependent silencing of these extracellular Wnt antagonists, including SFRP1, SFRP2, SFRP4 and SFRP5, correlates with constitutive activation of canonical Wnt/β-catenin signaling in liver cancers [48,49]. Among them, SFRP5 hepatic expression was recently reported to be associated with NAFLD in morbidly obese people [50], and the CpG methylation level of SFRP5 was inversely correlated with its expression in NAFLD patients [46]. These data showed that SFRP5 is functionally important and is under epigenetic regulation in NAFLD development.
SOX17 is a nuclear protein that directly interacts with TCF/LEF to inhibit the transcription of Wnt signaling target genes. Epigenetic silencing of SOX17 through promoter methylation is a frequent event in human cancers, and it contributes to the aberrant activation of Wnt/β-catenin signaling [51]. Moreover, SOX17 plays a key role in regulating insulin secretion, as mice lacking Sox17 were more susceptible to high fat diet-induced hyperglycemia and diabetes [52]. Functionally, hyperinsulinaemia may affect HCC development not only through direct effects on the growth of hepatocytes, but also indirectly by increasing the production of cytokines and mitogens, enhancing fibrosis and promoting angiogenesis [53]. Taken together, down-regulation of SOX17 via promoter methylation may promote Wnt activity and insulin secretion and thereby accelerate the progression from NAFLD to HCC.
The cytosolic Wnt antagonists, such as members of the DACT gene family (DACT2 and DACT3), can antagonize Dvl and are central components of Wnt signaling [54]. Zhang and colleagues found that DACT2 promoter methylation was inversely correlated with DACT2 expression, which could be restored by 5-aza-2′-deoxycytidine in HCC cell lines. Of clinical significance, reduced DACT2 expression was significantly related to promoter hypermethylation in 28 of 62 (45.16%) HCC patients, and the expression of DACT2 was inversely related to β-catenin expression in liver cancers [55]. Moreover hypermethylation of the DACT2 promoter was reported in advanced NAFLD individuals compared with mild NAFLD patients [46], which is consistent with its low expression in HCCs.
Distinct from DACT2, silencing of DACT3 in cancer cells is mediated by a bivalent histone modification that contains both repressive histone H3 lysine 27 trimethylation (H3K27me3) and activating H3K4me3, and such DACT3 ablation is not associated with promoter methylation [56]. Of note, it has been reported that histone modification and promoter methylation can independently regulate gene suppression [57], which illustrates the complexity of epigenetic controls on Wnt/β-catenin signaling pathway in liver cancers.

3.2. Histone Modifications

Based on previous studies, histone modification plays a key role in controlling the expression of Wnt inhibitors in HCC cells. Using chromatin immunoprecipitation microarray (ChIP-Chip) analysis, Cheng and colleagues discovered a panel of Wnt pathway inhibitors whose promoters were concordantly occupied by enhancer of zeste homolog 2 (EZH2) and H3K27me3 in HCC cells [14]. EZH2 is a histone methyltransferase that catalyzes the addition of methyl groups to histone H3 at lysine 27 hence inducing gene repression. Further analyses illustrated that EZH2-mediated transcriptional suppression of these Wnt signaling antagonists allows constitutive activation of Wnt/β-catenin signaling, which contributes to EZH2-driven cellular proliferation [14].
Additionally, Ezh2 was reported to directly suppress Wnt genes to facilitate adipogenesis in mice. The adipogenesis defects in cells with enzymatically inactive Ezh2 can be rescued by expression of adipogenic transcription factors PPARγ and C/EBPα, or inhibitors of Wnt/β-catenin signaling [58]. Taken together these data indicate that EZH2 plays a critical role in the pathogenesis of NAFLD/NASH, and is closely related to the HCC progression.
Additional studies demonstrated that EZH2 and HDACs work in concert at epigenetic level to reinforce the aberrant Wnt signaling activation in HCCs. Knock-down of EZH2 reduced the occupancy of HDAC1 at the promoters of Wnt antagonists in HCC cells [14]. Treatment of obese diabetic mice with a class I selective HDAC inhibitor enhanced oxidative metabolism in adipose tissue, and reduced body weight, glucose and insulin levels, indicating improved metabolism condition [59]. Consistently, HDAC1 was up-regulated in diabetes patients [60].
Another class I HDAC, HDAC8, was also reported to physically interact with EZH2 to contribute to the activation of Wnt/β-catenin signaling during HCC development [10]. HDAC8 has been recently reported to promote insulin resistance and activate Wnt/β-catenin pathway in a NAFLD-HCC mouse model treated with high fat high carbohydrate diet. Mechanistically, HDAC8 binds to the promoter regions of Wnt antagonists (AXIN2, NKD1, PPP2R2B and PRICKLE1) and promotes their silencing, and thereby increases the expression of a β-catenin target CCND1 that in turn induces p53/p21-mediated apoptosis and G2-M phase cell cycle arrest. Lentivirus-mediated silencing of HDAC8 in vivo was sufficient to reverse insulin resistance and reduce NAFLD-associated tumorigenicity. Furthermore, HDAC8 was directly up-regulated by the lipogenic transcription factor SREBP-1, and such positive relationship is highly consistent in dietary obesity models of NASH and HCC [10].
Taken together, these studies provide links between histone modification and Wnt/β-catenin signaling in the development of NAFLD-associated liver cancers.

3.3. MiRNAs

Emerging evidence suggests the role of miRNAs in the regulation of key biological properties of HCC [9,13,61]. In a recent study, a NAFLD-NASH HCC model was established by high fat diet. In this model, gross anatomical examination revealed differential hepatomegaly, and histological analysis showed different degrees and levels of steatosis, inflammatory infiltration and fibrosis in the high fat diet-treated animals compared with controls, demonstrating the progression from NAFLD to NASH. Importantly, macroscopic nodules were observed in 20% of high fat diet-fed mice after 12 months of treatment. Fifteen differentially expressed miRNAs was identified in high fat diet-treated mice with respect to controls. Among the identified miRNAs, miR-125a-5p showed up-regulation and miR-182 showed down-regulation in the progression from liver damage to liver cancer formation [62].
miR-122 is the most abundant miRNA in the adult human livers. It can bind to the 3′-UTR of Wnt1 mRNA for suppression, as well as down-regulating the protein levels of Wnt1, β-catenin and TCF-4. It was previously shown that miR-122 was under-expressed in HCC relative to normal liver tissue, suggesting that loss of miR-122 in HCC might contribute to excess Wnt signaling [63]. There are many direct and indirect targets of miR-122 involved in liver homeostasis, and the miR-122 expression was reported to be abnormal in most liver diseases [64]. miR-122 is considered to be a tumor suppressor miRNA, and recent study showed that mice lacking miR-122 were prone to quick development of steatohepatitis, fibrosis and HCC [65]. In addition to HCC, miR-122 expression was also reported to be dysregulated in ob/ob mouse livers [66]. It has been demonstrated that miR-370 induces the accumulation of hepatic triglycerides through miR122, which leads to increased expression of SREBP-1c and other genes controlling lipid metabolism [67]. Another study showed that hepatocytes from miR-122-depleted mice had higher fatty acid oxidation rates and less fatty acid synthesis [68]. Similarly, miR-122 antagonist significantly improved hepatic steatosis and reduced levels of triglyceride accumulation in diet-induced obese mice. Taken together, miR-122 is a risk factor of obesity and hepatic metabolic dysfunction. Moreover, hepatic miR-122 deregulation appears to contribute to NAFLD progression towards HCC, while circulating miR-122 levels correlate with disease stages and is thus a potential biomarker of NASH-HCC progression.
miR-34a was reported to be a tumor suppressor in HCCs through regulation of Wnt/β-catenin pathway. Studies showed that ectopic miR-34a induces cell-cycle arrest and apoptosis by down-regulation of CCND1 [69,70]. In turn, miR-34a was also found to be significantly up-regulated by the over-activation of β-catenin signaling in mouse tumors and in HCC patients [71]. In chronic hepatitis patients, serum levels of miR-34a were significantly higher than those in controls, and positively correlated with disease severity from simple steatosis to steatohepatitis [72].
Another tumor suppressor miR-145 targets insulin receptor substrate-1 (IRS-1) in the insulin-like growth factor pathway and regulates resistin-induced insulin resistance [73]. Down-regulation of miR-145 could be used to differentiate between steatosis and steatohepatitis in diet-induced NASH [74], indicating its critical role in NAFLD development. Increased miR-145 expression leads to the reduction of β-catenin protein levels, thus exhibiting its tumor suppressor function in HCC.
However, there are several miRNAs that showed opposite expression patterns in metabolic disorder and HCC. MiR-214 is a tumor suppressor miRNA that can directly or indirectly targets β-catenin to inhibit cell growth by down-regulating c-Myc, cyclin D1, TCF-1 and LEF1 in HCC [75]. However, miR-214 was found to be significantly up-regulated in ob/ob mouse livers compared with controls [66]. Further research is required for deeper understanding of the mechanisms underlying the contradictory functions of these miRNAs in NAFLD and HCC.

4. Clinical Implications

In this review, we have summarized the evidence that Wnt/β-catenin signaling is epigenetically dysregulated through multiple mechanisms in NAFLD-HCC (Table 1). Of clinical significance, some epigenetic changes are pharmacologically reversible using epigenetic agents including DNMT inhibitors (such as 5-aza) and HDAC inhibitors (such as TSA, SAHA) [76]. These epigenetic inhibitors have been reported as potential therapeutic agents with promising effects in various cancers [37]. For examples, restoration of the expression of Wnt antagonists through either DNA demethylation or histone remodeling results in the blockade of β-catenin-dependent transcription, inhibition of tumor cell proliferation, and induction of tumor cell apoptosis in HCC [10,14,55,77]; and pharmacological demethylation using 5-aza-2′-deoxycytidine leads to the demethylation and expression of SFRPs, DACT2 and WNT10B, reduction of TCF/β-catenin target genes, and apoptosis in cancer cells [55,77,78,79]. In addition, targeting noncoding RNAs that are deregulated in HCC and contribute to the tumor phenotype or tumor chemosensitivity is also a feasible approach. To date dozens of miRNAs and long noncoding RNAs (lncRNA) with specific roles in HCC development have been documented in the literature, and some of which were shown to be promising therapeutic targets. For instance, phase I and II clinical trials using anti-miR-122 oligonucleotides that target miR-122 have shown both the safety and efficacy of this approach in humans [80]. Although there is no study on the effect of these inhibitors in NAFLD progression, it is anticipated that epigenetic modulation of Wnt/β-catenin signaling is a rational approach and potentially an effective therapeutic strategy for treating Wnt- and NALFD-associated liver cancers.

Acknowledgments

This work was supported by the Collaborative Research Fund (C4017-14G) and General Research Fund (14102914) of the Hong Kong Research Grants Council, the National Natural Science Foundation of China (373492, 81302167, 81522030, and 91439132) and the National Program on Key Basic Research of China (973 Program No. 2015CB553705).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Villanueva, A.; Hernandez-Gea, V.; Llovet, J.M. Medical therapies for hepatocellular carcinoma: A critical view of the evidence. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 34–42. [Google Scholar] [CrossRef] [PubMed]
  2. Makarova-Rusher, O.V.; Altekruse, S.F.; McNeel, T.S.; Ulahannan, S.; Duffy, A.G.; Graubard, B.I.; Greten, T.F.; McGlynn, K.A. Population attributable fractions of risk factors for hepatocellular carcinoma in the united states. Cancer 2016, 122, 1757–1765. [Google Scholar] [CrossRef] [PubMed]
  3. Bhala, N.; Angulo, P.; van der Poorten, D.; Lee, E.; Hui, J.M.; Saracco, G.; Adams, L.A.; Charatcharoenwitthaya, P.; Topping, J.H.; Bugianesi, E.; et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: An international collaborative study. Hepatology 2011, 54, 1208–1216. [Google Scholar] [CrossRef] [PubMed]
  4. Farrell, G.C.; van Rooyen, D.; Gan, L.; Chitturi, S. Nash is an inflammatory disorder: Pathogenic, prognostic and therapeutic implications. Gut Liver 2012, 6, 149–171. [Google Scholar] [CrossRef] [PubMed]
  5. Yuen, M.F.; Tanaka, Y.; Fong, D.Y.; Fung, J.; Wong, D.K.; Yuen, J.C.; But, D.Y.; Chan, A.O.; Wong, B.C.; Mizokami, M.; et al. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis b. J. Hepatol. 2009, 50, 80–88. [Google Scholar] [CrossRef] [PubMed]
  6. Wong, V.W.; Chu, W.C.; Wong, G.L.; Chan, R.S.; Chim, A.M.; Ong, A.; Yeung, D.K.; Yiu, K.K.; Chu, S.H.; Woo, J.; et al. Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in hong kong chinese: A population study using proton-magnetic resonance spectroscopy and transient elastography. Gut 2012, 61, 409–415. [Google Scholar] [CrossRef] [PubMed]
  7. Haladyna, J.N.; Yamauchi, T.; Neff, T.; Bernt, K.M. Epigenetic modifiers in normal and malignant hematopoiesis. Epigenomics 2015, 7, 301–320. [Google Scholar] [CrossRef] [PubMed]
  8. Dawson, M.A.; Kouzarides, T. Cancer epigenetics: From mechanism to therapy. Cell 2012, 150, 12–27. [Google Scholar] [CrossRef]
  9. Tsang, D.P.; Wu, W.K.; Kang, W.; Lee, Y.Y.; Wu, F.; Yu, Z.; Xiong, L.; Chan, A.W.; Tong, J.H.; Yang, W.; et al. Yin yang 1-mediated epigenetic silencing of tumour-suppressive micrornas activates nuclear factor-kappab in hepatocellular carcinoma. J. Pathol. 2016, 238, 651–664. [Google Scholar] [CrossRef] [PubMed]
  10. Tian, Y.; Wong, V.W.; Wong, G.L.; Yang, W.; Sun, H.; Shen, J.; Tong, J.H.; Go, M.Y.; Cheung, Y.S.; Lai, P.B.; et al. Histone deacetylase hdac8 promotes insulin resistance and beta-catenin activation in nafld-associated hepatocellular carcinoma. Cancer Res. 2015, 75, 4803–4816. [Google Scholar] [CrossRef] [PubMed]
  11. Feng, H.; Yu, Z.; Tian, Y.; Lee, Y.Y.; Li, M.S.; Go, M.Y.; Cheung, Y.S.; Lai, P.B.; Chan, A.M.; To, K.F.; et al. A ccrk-ezh2 epigenetic circuitry drives hepatocarcinogenesis and associates with tumor recurrence and poor survival of patients. J. Hepatol. 2015, 62, 1100–1111. [Google Scholar] [CrossRef] [PubMed]
  12. Zhang, B.; Chen, J.; Cheng, A.S.; Ko, B.C. Depletion of sirtuin 1 (sirt1) leads to epigenetic modifications of telomerase (tert) gene in hepatocellular carcinoma cells. PLoS ONE 2014, 9, e84931. [Google Scholar] [CrossRef] [PubMed]
  13. Yip, W.K.; Cheng, A.S.; Zhu, R.; Lung, R.W.; Tsang, D.P.; Lau, S.S.; Chen, Y.; Sung, J.G.; Lai, P.B.; Ng, E.K.; et al. Carboxyl-terminal truncated hbx regulates a distinct microrna transcription program in hepatocellular carcinoma development. PLoS ONE 2011, 6, e22888. [Google Scholar] [CrossRef] [PubMed][Green Version]
  14. Cheng, A.S.; Lau, S.S.; Chen, Y.; Kondo, Y.; Li, M.S.; Feng, H.; Ching, A.K.; Cheung, K.F.; Wong, H.K.; Tong, J.H.; et al. Ezh2-mediated concordant repression of wnt antagonists promotes beta-catenin-dependent hepatocarcinogenesis. Cancer Res. 2011, 71, 4028–4039. [Google Scholar] [CrossRef] [PubMed]
  15. Tian, Y.; Wong, V.W.; Chan, H.L.; Cheng, A.S. Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease. Semin. Cancer Biol. 2013, 23, 471–482. [Google Scholar] [CrossRef] [PubMed]
  16. Ahrens, M.; Ammerpohl, O.; von Schonfels, W.; Kolarova, J.; Bens, S.; Itzel, T.; Teufel, A.; Herrmann, A.; Brosch, M.; Hinrichsen, H.; et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 2013, 18, 296–302. [Google Scholar] [CrossRef] [PubMed]
  17. Pogribny, I.P.; Tryndyak, V.P.; Bagnyukova, T.V.; Melnyk, S.; Montgomery, B.; Ross, S.A.; Latendresse, J.R.; Rusyn, I.; Beland, F.A. Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet. J. Hepatol. 2009, 51, 176–186. [Google Scholar] [CrossRef] [PubMed]
  18. Ammerpohl, O.; Pratschke, J.; Schafmayer, C.; Haake, A.; Faber, W.; von Kampen, O.; Brosch, M.; Sipos, B.; von Schonfels, W.; Balschun, K.; et al. Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma. Int. J. Cancer 2012, 130, 1319–1328. [Google Scholar] [CrossRef] [PubMed]
  19. Drong, A.W.; Lindgren, C.M.; McCarthy, M.I. The genetic and epigenetic basis of type 2 diabetes and obesity. Clin. Pharmacol. Ther. 2012, 92, 707–715. [Google Scholar] [CrossRef] [PubMed]
  20. Relton, C.L.; Groom, A.; St Pourcain, B.; Sayers, A.E.; Swan, D.C.; Embleton, N.D.; Pearce, M.S.; Ring, S.M.; Northstone, K.; Tobias, J.H.; et al. DNA methylation patterns in cord blood DNA and body size in childhood. PLoS ONE 2012, 7, e31821. [Google Scholar] [CrossRef] [PubMed][Green Version]
  21. Alenghat, T.; Meyers, K.; Mullican, S.E.; Leitner, K.; Adeniji-Adele, A.; Avila, J.; Bucan, M.; Ahima, R.S.; Kaestner, K.H.; Lazar, M.A. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 2008, 456, 997–1000. [Google Scholar] [CrossRef] [PubMed]
  22. Feng, D.; Liu, T.; Sun, Z.; Bugge, A.; Mullican, S.E.; Alenghat, T.; Liu, X.S.; Lazar, M.A. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 2011, 331, 1315–1319. [Google Scholar] [CrossRef] [PubMed]
  23. Sun, Z.; Miller, R.A.; Patel, R.T.; Chen, J.; Dhir, R.; Wang, H.; Zhang, D.; Graham, M.J.; Unterman, T.G.; Shulman, G.I.; et al. Hepatic HDAC3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 2012, 18, 934–942. [Google Scholar] [CrossRef] [PubMed]
  24. Rottiers, V.; Naar, A.M. Micrornas in metabolism and metabolic disorders. Nat. Rev. Mol. Cell Biol. 2012, 13, 239–250. [Google Scholar] [CrossRef] [PubMed]
  25. Jordan, S.D.; Kruger, M.; Willmes, D.M.; Redemann, N.; Wunderlich, F.T.; Bronneke, H.S.; Merkwirth, C.; Kashkar, H.; Olkkonen, V.M.; Bottger, T.; et al. Obesity-induced overexpression of mirna-143 inhibits insulin-stimulated akt activation and impairs glucose metabolism. Nat. Cell Biol. 2011, 13, 434–446. [Google Scholar] [CrossRef] [PubMed]
  26. Rayner, K.J.; Esau, C.C.; Hussain, F.N.; McDaniel, A.L.; Marshall, S.M.; van Gils, J.M.; Ray, T.D.; Sheedy, F.J.; Goedeke, L.; Liu, X.; et al. Inhibition of mir-33a/b in non-human primates raises plasma hdl and lowers VLDL triglycerides. Nature 2011, 478, 404–407. [Google Scholar] [CrossRef] [PubMed]
  27. Trajkovski, M.; Hausser, J.; Soutschek, J.; Bhat, B.; Akin, A.; Zavolan, M.; Heim, M.H.; Stoffel, M. Micrornas 103 and 107 regulate insulin sensitivity. Nature 2011, 474, 649–653. [Google Scholar] [CrossRef] [PubMed]
  28. Calin, G.A.; Croce, C.M. Microrna signatures in human cancers. Nat. Rev. Cancer 2006, 6, 857–866. [Google Scholar] [CrossRef] [PubMed]
  29. Shen, J.; Xiao, Z.; Wu, W.K.; Wang, M.H.; To, K.F.; Chen, Y.; Yang, W.; Li, M.S.; Shin, V.Y.; Tong, J.H.; et al. Epigenetic silencing of mir-490-3p reactivates the chromatin remodeler smarcd1 to promote helicobacter pylori-induced gastric carcinogenesis. Cancer Res. 2015, 75, 754–765. [Google Scholar] [CrossRef] [PubMed]
  30. Kang, W.; Tong, J.H.; Lung, R.W.; Dong, Y.; Zhao, J.; Liang, Q.; Zhang, L.; Pan, Y.; Yang, W.; Pang, J.C.; et al. Targeting of yap1 by microrna-15a and microrna-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol. Cancer 2015. [Google Scholar] [CrossRef] [PubMed]
  31. Llovet, J.M.; Villanueva, A.; Lachenmayer, A.; Finn, R.S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat. Rev. Clin. Oncol. 2015. [Google Scholar] [CrossRef] [PubMed]
  32. Mok, M.T.; Cheng, A.S. Cul4b: A novel epigenetic driver in wnt/beta-catenin-dependent hepatocarcinogenesis. J. Pathol. 2015, 236, 1–4. [Google Scholar] [CrossRef] [PubMed]
  33. Yuan, J.; Han, B.; Hu, H.; Qian, Y.; Liu, Z.; Wei, Z.; Liang, X.; Jiang, B.; Shao, C.; Gong, Y. Cul4b activates wnt/beta-catenin signaling in hepatocellular carcinoma by repressing wnt antagonists. J. Pathol. 2015, 135, 784–795. [Google Scholar] [CrossRef] [PubMed]
  34. Liu, C.; Li, Y.; Semenov, M.; Han, C.; Baeg, G.H.; Tan, Y.; Zhang, Z.; Lin, X.; He, X. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 2002, 108, 837–847. [Google Scholar] [CrossRef]
  35. Kimelman, D.; Xu, W. Beta-catenin destruction complex: Insights and questions from a structural perspective. Oncogene 2006, 25, 7482–7491. [Google Scholar] [CrossRef] [PubMed]
  36. Patil, M.A.; Lee, S.A.; Macias, E.; Lam, E.T.; Xu, C.; Jones, K.D.; Ho, C.; Rodriguez-Puebla, M.; Chen, X. Role of cyclin d1 as a mediator of c-met- and beta-catenin-induced hepatocarcinogenesis. Cancer Res. 2009, 69, 253–261. [Google Scholar] [CrossRef] [PubMed]
  37. Baylin, S.B.; Ohm, J.E. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat. Rev. Cancer 2006, 6, 107–116. [Google Scholar] [CrossRef] [PubMed]
  38. Tetsu, O.; McCormick, F. Beta-catenin regulates expression of cyclin d1 in colon carcinoma cells. Nature 1999, 398, 422–426. [Google Scholar] [PubMed]
  39. Liu, F.; Dong, X.; Lv, H.; Xiu, P.; Li, T.; Wang, F.; Xu, Z.; Li, J. Targeting hypoxia-inducible factor-2alpha enhances sorafenib antitumor activity via beta-catenin/C-myc-dependent pathways in hepatocellular carcinoma. Oncol. Lett. 2015, 10, 778–784. [Google Scholar] [PubMed]
  40. Ying, Y.; Tao, Q. Epigenetic disruption of the Wnt/beta-catenin signaling pathway in human cancers. Epigenetics 2009, 4, 307–312. [Google Scholar] [CrossRef] [PubMed]
  41. MacDonald, B.T.; Tamai, K.; He, X. Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev. Cell 2009, 17, 9–26. [Google Scholar] [CrossRef] [PubMed]
  42. Barker, N.; Clevers, H. Mining the Wnt pathway for cancer therapeutics. Nat. Rev. Drug Discov. 2006, 5, 997–1014. [Google Scholar] [CrossRef] [PubMed]
  43. Cui, J.; Zhou, X.; Liu, Y.; Tang, Z.; Romeih, M. Wnt signaling in hepatocellular carcinoma: Analysis of mutation and expression of beta-catenin, t-cell factor-4 and glycogen synthase kinase 3-beta genes. J. Gastroenterol. Hepatol. 2003, 18, 280–287. [Google Scholar] [CrossRef] [PubMed]
  44. Ishizaki, Y.; Ikeda, S.; Fujimori, M.; Shimizu, Y.; Kurihara, T.; Itamoto, T.; Kikuchi, A.; Okajima, M.; Asahara, T. Immunohistochemical analysis and mutational analyses of beta-catenin, axin family and apc genes in hepatocellular carcinomas. Int. J. Oncol. 2004, 24, 1077–1083. [Google Scholar] [PubMed]
  45. Chan, D.W.; Chan, C.Y.; Yam, J.W.; Ching, Y.P.; Ng, I.O. Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting dishevelled ubiquitination/degradation in liver cancer. Gastroenterology 2006, 131, 1218–1227. [Google Scholar] [CrossRef] [PubMed]
  46. Murphy, S.K.; Yang, H.; Moylan, C.A.; Pang, H.; Dellinger, A.; Abdelmalek, M.F.; Garrett, M.E.; Ashley-Koch, A.; Suzuki, A.; Tillmann, H.L.; et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 2013, 145, 1076–1087. [Google Scholar] [CrossRef] [PubMed]
  47. Kawano, Y.; Kypta, R. Secreted antagonists of the wnt signalling pathway. J. Cell Sci. 2003, 116, 2627–2634. [Google Scholar] [CrossRef] [PubMed]
  48. Kaur, P.; Mani, S.; Cros, M.P.; Scoazec, J.Y.; Chemin, I.; Hainaut, P.; Herceg, Z. Epigenetic silencing of sfrp1 activates the canonical Wnt pathway and contributes to increased cell growth and proliferation in hepatocellular carcinoma. Tumour Biol. 2012, 33, 325–336. [Google Scholar] [CrossRef] [PubMed]
  49. Takagi, H.; Sasaki, S.; Suzuki, H.; Toyota, M.; Maruyama, R.; Nojima, M.; Yamamoto, H.; Omata, M.; Tokino, T.; Imai, K.; et al. Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma. J. Gastroenterol. 2008, 43, 378–389. [Google Scholar] [CrossRef] [PubMed]
  50. Gutierrez-Vidal, R.; Vega-Badillo, J.; Reyes-Fermin, L.M.; Hernandez-Perez, H.A.; Sanchez-Munoz, F.; Lopez-Alvarez, G.S.; Larrieta-Carrasco, E.; Fernandez-Silva, I.; Mendez-Sanchez, N.; Tovar, A.R.; et al. SFRP5 hepatic expression is associated with non-alcoholic liver disease in morbidly obese women. Ann. Hepatol. 2015, 14, 666–674. [Google Scholar] [PubMed]
  51. Jia, Y.; Yang, Y.; Liu, S.; Herman, J.G.; Lu, F.; Guo, M. Sox17 antagonizes Wnt/beta-catenin signaling pathway in hepatocellular carcinoma. Epigenetics 2010, 5, 743–749. [Google Scholar] [CrossRef] [PubMed]
  52. Jonatan, D.; Spence, J.R.; Method, A.M.; Kofron, M.; Sinagoga, K.; Haataja, L.; Arvan, P.; Deutsch, G.H.; Wells, J.M. Sox17 regulates insulin secretion in the normal and pathologic mouse beta cell. PLoS ONE 2014, 9, e104675. [Google Scholar] [CrossRef] [PubMed]
  53. Chettouh, H.; Lequoy, M.; Fartoux, L.; Vigouroux, C.; Desbois-Mouthon, C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int. 2015, 35, 2203–2217. [Google Scholar] [CrossRef] [PubMed]
  54. Cheyette, B.N.; Waxman, J.S.; Miller, J.R.; Takemaru, K.; Sheldahl, L.C.; Khlebtsova, N.; Fox, E.P.; Earnest, T.; Moon, R.T. Dapper, a dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. Dev. Cell 2002, 2, 449–461. [Google Scholar] [CrossRef]
  55. Zhang, X.; Yang, Y.; Liu, X.; Herman, J.G.; Brock, M.V.; Licchesi, J.D.; Yue, W.; Pei, X.; Guo, M. Epigenetic regulation of the Wnt signaling inhibitor DACT2 in human hepatocellular carcinoma. Epigenetics 2013, 8, 373–382. [Google Scholar] [CrossRef] [PubMed]
  56. Jiang, X.; Tan, J.; Li, J.; Kivimae, S.; Yang, X.; Zhuang, L.; Lee, P.L.; Chan, M.T.; Stanton, L.W.; Liu, E.T.; et al. DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell 2008, 13, 529–541. [Google Scholar] [CrossRef] [PubMed]
  57. Kondo, Y.; Shen, L.; Cheng, A.S.; Ahmed, S.; Boumber, Y.; Charo, C.; Yamochi, T.; Urano, T.; Furukawa, K.; Kwabi-Addo, B.; et al. Gene silencing in cancer by histone h3 lysine 27 trimethylation independent of promoter DNA methylation. Nature Genet. 2008, 40, 741–750. [Google Scholar] [CrossRef] [PubMed]
  58. Wang, L.; Jin, Q.; Lee, J.E.; Su, I.H.; Ge, K. Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc. Natl. Acad. Sci. USA 2010, 107, 7317–7322. [Google Scholar] [CrossRef] [PubMed]
  59. Galmozzi, A.; Mitro, N.; Ferrari, A.; Gers, E.; Gilardi, F.; Godio, C.; Cermenati, G.; Gualerzi, A.; Donetti, E.; Rotili, D.; et al. Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue. Diabetes 2013, 62, 732–742. [Google Scholar] [CrossRef] [PubMed]
  60. Liu, X.Y.; Xu, J.F. Reduced histone H3 acetylation in CD4(+) t lymphocytes: Potential mechanism of latent autoimmune diabetes in adults. Dis. Markers 2015. [Google Scholar] [CrossRef] [PubMed]
  61. Yu, Z.; Cheng, A.S. Epigenetic deregulation of micrornas: New opportunities to target oncogenic signaling pathways in hepatocellular carcinoma. Curr. Pharm. Des. 2013, 19, 1192–1200. [Google Scholar] [PubMed]
  62. Tessitore, A.; Cicciarelli, G.; Del Vecchio, F.; Gaggiano, A.; Verzella, D.; Fischietti, M.; Mastroiaco, V.; Vetuschi, A.; Sferra, R.; Barnabei, R.; et al. Microrna expression analysis in high fat diet-induced nafld-nash-hcc progression: Study on C57BL/6J mice. BMC Cancer 2016. [Google Scholar] [CrossRef] [PubMed]
  63. Xu, J.; Zhu, X.; Wu, L.; Yang, R.; Yang, Z.; Wang, Q.; Wu, F. Microrna-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/beta-catenin pathway. Liver Int. 2012, 32, 752–760. [Google Scholar] [CrossRef] [PubMed]
  64. Bandiera, S.; Pfeffer, S.; Baumert, T.F.; Zeisel, M.B. Mir-122––A key factor and therapeutic target in liver disease. J. Hepatol. 2015, 62, 448–457. [Google Scholar] [CrossRef] [PubMed]
  65. Hsu, S.H.; Wang, B.; Kota, J.; Yu, J.; Costinean, S.; Kutay, H.; Yu, L.; Bai, S.; La Perle, K.; Chivukula, R.R.; et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of mir-122 in liver. J. Clin. Invest. 2012, 122, 2871–2883. [Google Scholar] [CrossRef] [PubMed]
  66. Liang, T.; Liu, C.; Ye, Z. Deep sequencing of small rna repertoires in mice reveals metabolic disorders-associated hepatic mirnas. PLoS ONE 2013, 8, e80774. [Google Scholar] [CrossRef] [PubMed]
  67. Iliopoulos, D.; Drosatos, K.; Hiyama, Y.; Goldberg, I.J.; Zannis, V.I. MicroRNA-370 controls the expression of microRNA-122 and CPT1alpha and affects lipid metabolism. J. Lipid Res. 2010, 51, 1513–1523. [Google Scholar] [CrossRef] [PubMed]
  68. Esau, C.; Davis, S.; Murray, S.F.; Yu, X.X.; Pandey, S.K.; Pear, M.; Watts, L.; Booten, S.L.; Graham, M.; McKay, R.; et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006, 3, 87–98. [Google Scholar] [CrossRef] [PubMed]
  69. Sun, F.; Fu, H.; Liu, Q.; Tie, Y.; Zhu, J.; Xing, R.; Sun, Z.; Zheng, X. Downregulation of ccnd1 and CDK6 by miR-34a induces cell cycle arrest. FEBS Lett. 2008, 582, 1564–1568. [Google Scholar] [CrossRef] [PubMed]
  70. Cheng, J.; Zhou, L.; Xie, Q.F.; Xie, H.Y.; Wei, X.Y.; Gao, F.; Xing, C.Y.; Xu, X.; Li, L.J.; Zheng, S.S. The impact of miR-34a on protein output in hepatocellular carcinoma HepG2 cells. Proteomics 2010, 10, 1557–1572. [Google Scholar] [CrossRef] [PubMed]
  71. Gougelet, A.; Sartor, C.; Bachelot, L.; Godard, C.; Marchiol, C.; Renault, G.; Tores, F.; Nitschke, P.; Cavard, C.; Terris, B.; et al. Antitumour activity of an inhibitor of miR-34a in liver cancer with beta-catenin-mutations. Gut 2015, 65, 1024–1034. [Google Scholar] [CrossRef] [PubMed]
  72. Afonso, M.B.; Rodrigues, P.M.; Simao, A.L.; Castro, R.E. Circulating micrornas as potential biomarkers in non-alcoholic fatty liver disease and hepatocellular carcinoma. J. Clin. Med. 2016. [Google Scholar] [CrossRef] [PubMed]
  73. Wen, F.; Yang, Y.; Jin, D.; Sun, J.; Yu, X.; Yang, Z. miRNA-145 is involved in the development of resistin-induced insulin resistance in HepG2 cells. Biochem. Biophys. Res. Commun. 2014, 445, 517–523. [Google Scholar] [CrossRef] [PubMed]
  74. Jin, X.; Chen, Y.P.; Kong, M.; Zheng, L.; Yang, Y.D.; Li, Y.M. Transition from hepatic steatosis to steatohepatitis: Unique microRNA patterns and potential downstream functions and pathways. J. Gastroenterol. Hepatol. 2012, 27, 331–340. [Google Scholar] [CrossRef] [PubMed]
  75. Xia, H.; Ooi, L.L.; Hui, K.M. miR-214 targets beta-catenin pathway to suppress invasion, stem-like traits and recurrence of human hepatocellular carcinoma. PLoS ONE 2012, 7, e44206. [Google Scholar]
  76. Oronsky, B.; Oronsky, N.; Knox, S.; Fanger, G.; Scicinski, J. Episensitization: Therapeutic tumor resensitization by epigenetic agents: A review and reassessment. Anticancer Agents Med. Chem. 2014, 14, 1121–1127. [Google Scholar] [CrossRef] [PubMed]
  77. Lin, Y.W.; Shih, Y.L.; Lien, G.S.; Suk, F.M.; Hsieh, C.B.; Yan, M.D. Promoter methylation of SFRP3 is frequent in hepatocellular carcinoma. Dis. Markers 2014. [Google Scholar] [CrossRef] [PubMed]
  78. Yoshikawa, H.; Matsubara, K.; Zhou, X.; Okamura, S.; Kubo, T.; Murase, Y.; Shikauchi, Y.; Esteller, M.; Herman, J.G.; Wei Wang, X.; et al. Wnt10b functional dualism: Beta-catenin/TCF-dependent growth promotion or independent suppression with deregulated expression in cancer. Mol. Biol. Cell 2007, 18, 4292–4303. [Google Scholar] [CrossRef] [PubMed]
  79. Quan, H.; Zhou, F.; Nie, D.; Chen, Q.; Cai, X.; Shan, X.; Zhou, Z.; Chen, K.; Huang, A.; Li, S.; et al. Hepatitis C virus core protein epigenetically silences SFRP1 and enhances HCC aggressiveness by inducing epithelial-mesenchymal transition. Oncogene 2014, 33, 2826–2835. [Google Scholar] [CrossRef] [PubMed]
  80. George, J.; Patel, T. Noncoding rna as therapeutic targets for hepatocellular carcinoma. Semin. Liver Dis. 2015, 35, 63–74. [Google Scholar] [CrossRef] [PubMed]
Table 1. Epigentic regulations of Wnt/β-catenin signaling in NAFLD-HCC.
Table 1. Epigentic regulations of Wnt/β-catenin signaling in NAFLD-HCC.
Epigenetic RegulationGene NameEpigenetic ChangesRoles in Wnt/β-CateninRoles in NAFLDRoles in HCCReferences
DNA methylationSFRP5HypermethylationPrevent ligand-receptor interactionsDown-regulated in obese people with non-alcoholic liver diseaseDown-regulated in HCC patients[46,47,48]
SOX17HypermethylationInteract with the nuclear transcription complex TCF/LEFRegulate insulin secretion in miceDown-regulated in HCC patients[51,52]
DACT2HypermethylationAntagonize DvlHypermethylated promoter in advanced NAFLD patientsDown-regulated in HCC patients[54,55]
Histone modificationEZH2H3K27 trimethylationSuppress AXIN2, NKD1, PPP2R2B, PRICKLE1 and SFRP5Up-regulated in NAFLD-HCC patients and mouse modelUp-regulated in HCC patients[10,14,58]
HDAC1Interaction with EZH2Suppress AXIN2, NKD1, PPP2R2B, PRICKLE1 and SFRP5Class I selective HDAC inhibitor reduces body weight, and glucose and insulin levels in miceUp-regulated in HCC patients[14,59,60]
HDAC8Interaction with EZH2, H4 acetylationSuppress AXIN2, NKD1, PPP2R2B and PRICKLE1Up-regulated in NAFLD-HCC patients and mouse modelUp-regulated in NAFLD-HCC patients[10]
MicroRNAsmiR-122Down-regulationSuppress Wnt1 activityIncreased fatty acid oxidation rates and reduced fatty acid synthesisDown-regulated in HCC patients[63,64,65,66,67,68]
miR-34aDown-regulationInduce cyclin D1 expressionIncreased at serum levels in NAFLD patientsDown-regulated in HCC patients[69,70,71,72]
miR-145Down-regulationReduce β-catenin levelsDown-regulated in mouse modelDown-regulated in HCC patients[73,74]
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