RSS-Feed abonnieren
DOI: 10.1055/s-0037-1607451
Multifunctional YY1 in Liver Diseases
Publikationsverlauf
Publikationsdatum:
22. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/sld/201704/lookinside/thumbnails/10-1055-s-0037-1607451_1700041-1.jpg)
Abstract
The transcription factor Yin Yang 1 (YY1) is a multifunctional protein that can activate or repress gene expression, depending on the cellular context. While YY1 is ubiquitously expressed and highly conserved between species, its role varies among the diverse cell types and includes proliferation, differentiation, and apoptosis. Upregulated YY1 expression is found in pathogenic conditions, such as human hepatocellular carcinoma and hepatitis B virus infection, and its roles in the molecular pathogenic mechanisms in liver (i.e., fibrosis, carcinogenesis, viral-induced injury) are currently being elucidated. The most recent studies have revealed that YY1 is deeply involved in such dysregulated cellular metabolisms as glycometabolism, lipid metabolism, and bile acid metabolism, which are all involved in various diseases. In this review, we will summarize the current knowledge on YY1 in liver diseases, providing a focused discussion on the characterized and probable underlying mechanisms, as well as a reasoned evaluation of the potential for YY1-mediated pathology as drug targets in liver disease therapies.
* Authors contributed equally to this work.
-
References
- 1 Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015; 62 (1, Suppl) S47-S64
- 2 A brighter future in the fight against hepatitis. Nat Med 2013; 19 (07) 791
- 3 Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115 (02) 209-218
- 4 Mokdad AA, Lopez AD, Shahraz S. , et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med 2014; 12: 145
- 5 Shi J, Hao A, Zhang Q, Sui G. The role of YY1 in oncogenesis and its potential as a drug target in cancer therapies. Curr Cancer Drug Targets 2015; 15 (02) 145-157
- 6 Donohoe ME, Zhang X, McGinnis L, Biggers J, Li E, Shi Y. Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality. Mol Cell Biol 1999; 19 (10) 7237-7244
- 7 Gordon S, Akopyan G, Garban H, Bonavida B. Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene 2006; 25 (08) 1125-1142
- 8 Shang J, Zheng Y, Guo X. , et al. Hepatitis B virus replication and sex-determining region Y box 4 production are tightly controlled by a novel positive feedback mechanism. Sci Rep 2015; 5: 10066
- 9 Huang WH, Mai RT, Lee YH. Transcription factor YY1 and its associated acetyltransferases CBP and p300 interact with hepatitis delta antigens and modulate hepatitis delta virus RNA replication. J Virol 2008; 82 (15) 7313-7324
- 10 Riquet FB, Tan L, Choy BK. , et al. YY1 is a positive regulator of transcription of the Col1a1 gene. J Biol Chem 2001; 276 (42) 38665-38672
- 11 Galvin KM, Shi Y. Multiple mechanisms of transcriptional repression by YY1. Mol Cell Biol 1997; 17 (07) 3723-3732
- 12 Yant SR, Zhu W, Millinoff D, Slightom JL, Goodman M, Gumucio DL. High affinity YY1 binding motifs: identification of two core types (ACAT and CCAT) and distribution of potential binding sites within the human beta globin cluster. Nucleic Acids Res 1995; 23 (21) 4353-4362
- 13 Deng Z, Cao P, Wan MM, Sui G. Yin Yang 1: a multifaceted protein beyond a transcription factor. Transcription 2010; 1 (02) 81-84
- 14 Thomas MJ, Seto E. Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key?. Gene 1999; 236 (02) 197-208
- 15 Nguyen N, Zhang X, Olashaw N, Seto E. Molecular cloning and functional characterization of the transcription factor YY2. J Biol Chem 2004; 279 (24) 25927-25934
- 16 Lee HY, Chaudhary J, Walsh GL, Hong WK, Kurie JM. Suppression of c-Fos gene transcription with malignant transformation of human bronchial epithelial cells. Oncogene 1998; 16 (23) 3039-3046
- 17 Nakanishi-Matsui M, Hayashi Y, Kitamura Y, Koike K. Integrated hepatitis B virus DNA preserves the binding sequence of transcription factor Yin and Yang 1 at the virus-cell junction. J Virol 2000; 74 (12) 5562-5568
- 18 Notarbartolo M, Giannitrapani L, Vivona N. , et al. Frequent alteration of the Yin Yang 1/Raf-1 kinase inhibitory protein ratio in hepatocellular carcinoma. OMICS 2011; 15 (05) 267-272
- 19 Yano Y, Utsumi T, Lusida MI, Hayashi Y. Hepatitis B virus infection in Indonesia. World J Gastroenterol 2015; 21 (38) 10714-10720
- 20 Gerlich WH. Medical virology of hepatitis B: how it began and where we are now. Virol J 2013; 10: 239
- 21 Yang W, Mason WS, Summers J. Covalently closed circular viral DNA formed from two types of linear DNA in woodchuck hepatitis virus-infected liver. J Virol 1996; 70 (07) 4567-4575
- 22 Yang W, Summers J. Infection of ducklings with virus particles containing linear double-stranded duck hepatitis B virus DNA: illegitimate replication and reversion. J Virol 1998; 72 (11) 8710-8717
- 23 Hayashi Y, Kitamura Y, Nakanishi M, Koike K. The binding site of transcription factor YY1 is required for intramolecular recombination between terminally repeated sequences of linear replicative hepatitis B virus DNA. J Virol 2000; 74 (20) 9471-9478
- 24 Huang YW, Liu JC, Deatherage DE. , et al. Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. Cancer Res 2009; 69 (23) 9038-9046
- 25 Zhang S, Kim K, Jin UH. , et al. Aryl hydrocarbon receptor agonists induce microRNA-335 expression and inhibit lung metastasis of estrogen receptor negative breast cancer cells. Mol Cancer Ther 2012; 11 (01) 108-118
- 26 Shan X, Ren M, Chen K, Huang A, Tang H. Regulation of the microRNA processor DGCR8 by hepatitis B virus proteins via the transcription factor YY1. Arch Virol 2015; 160 (03) 795-803
- 27 Degasperi E, Aghemo A, Colombo M. Treatment of Extrahepatic Manifestations of Hepatitis C Virus. Clin Liver Dis 2017; 21 (03) 631-643
- 28 Lempp FA, Ni Y, Urban S. Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nat Rev Gastroenterol Hepatol 2016; 13 (10) 580-589
- 29 Friedman SL. Hepatic fibrosis: emerging therapies. Dig Dis 2015; 33 (04) 504-507
- 30 Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 2011; 6: 425-456
- 31 Natarajan V, Harris EN, Kidambi S. SECs (sinusoidal endothelial cells), liver microenvironment, and fibrosis. BioMed Res Int 2017; 2017: 4097205
- 32 Karsenty G, de Crombrugghe B. Two different negative and one positive regulatory factors interact with a short promoter segment of the alpha 1 (I) collagen gene. J Biol Chem 1990; 265 (17) 9934-9942
- 33 Saarela J, Rehn M, Oikarinen A, Autio-Harmainen H, Pihlajaniemi T. The short and long forms of type XVIII collagen show clear tissue specificities in their expression and location in basement membrane zones in humans. Am J Pathol 1998; 153 (02) 611-626
- 34 Saarela J, Ylikärppä R, Rehn M, Purmonen S, Pihlajaniemi T. Complete primary structure of two variant forms of human type XVIII collagen and tissue-specific differences in the expression of the corresponding transcripts. Matrix Biol 1998; 16 (06) 319-328
- 35 Armelin-Correa LM, Lin CJ, Barbosa A. , et al. Characterization of human collagen XVIII promoter 2: interaction of Sp1, Sp3 and YY1 with the regulatory region and a SNP that increases transcription in hepatocytes. Matrix Biol 2005; 24 (08) 550-559
- 36 Assy N, Minuk GY. Liver regeneration: methods for monitoring and their applications. J Hepatol 1997; 26 (04) 945-952
- 37 Moriya K, Sakai K, Yan MH, Sakai T. Fibronectin is essential for survival but is dispensable for proliferation of hepatocytes in acute liver injury in mice. Hepatology 2012; 56 (01) 311-321
- 38 Diamond RH, Du K, Lee VM. , et al. Novel delayed-early and highly insulin-induced growth response genes. Identification of HRS, a potential regulator of alternative pre-mRNA splicing. J Biol Chem 1993; 268 (20) 15185-15192
- 39 Du K, Leu JI, Peng Y, Taub R. Transcriptional up-regulation of the delayed early gene HRS/SRp40 during liver regeneration. Interactions among YY1, GA-binding proteins, and mitogenic signals. J Biol Chem 1998; 273 (52) 35208-35215
- 40 Shi Y, Seto E, Chang LS, Shenk T. Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein. Cell 1991; 67 (02) 377-388
- 41 Zhao X, Parpart S, Takai A. , et al. Integrative genomics identifies YY1AP1 as an oncogenic driver in EpCAM(+) AFP(+) hepatocellular carcinoma. Oncogene 2015; 34 (39) 5095-5104
- 42 Tsang DP, Wu WK, Kang W. , et al. Yin Yang 1-mediated epigenetic silencing of tumour-suppressive microRNAs activates nuclear factor-κB in hepatocellular carcinoma. J Pathol 2016; 238 (05) 651-664
- 43 Mai RT, Yeh TS, Kao CF, Sun SK, Huang HH, Wu Lee YH. Hepatitis C virus core protein recruits nucleolar phosphoprotein B23 and coactivator p300 to relieve the repression effect of transcriptional factor YY1 on B23 gene expression. Oncogene 2006; 25 (03) 448-462
- 44 Wang H, Yuan G, Zhao B, Zhao Y, Qiu Y. High expression of B23 is associated with tumorigenesis and poor prognosis in bladder urothelial carcinoma. Mol Med Rep 2017; 15 (02) 743-749
- 45 Zhou F, Chen E, You D, Song Y, Sun Z, Yue L. Both high expression of nucleophosmin/B23 and CRM1 predicts poorer prognosis in human gastric cancer. APMIS 2016; 124 (12) 1046-1053
- 46 Avdalyan AM, Kobyakov DS, Klimachev VV. , et al. Expression of B23/nucleophosphamine nonribosomal nucleolar protein in smooth muscle tumors of the corpus uteri. Bull Exp Biol Med 2015; 160 (02) 286-290
- 47 Yamashita T, Forgues M, Wang W. , et al. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 2008; 68 (05) 1451-1461
- 48 Yamashita T, Budhu A, Forgues M, Wang XW. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res 2007; 67 (22) 10831-10839
- 49 Yamashita T, Ji J, Budhu A. , et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 2009; 136 (03) 1012-1024
- 50 Kondo Y, Shen L, Cheng AS. , et al. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat Genet 2008; 40 (06) 741-750
- 51 Zhang S, Jiang T, Feng L. , et al. Yin Yang-1 suppresses differentiation of hepatocellular carcinoma cells through the downregulation of CCAAT/enhancer-binding protein alpha. J Mol Med (Berl) 2012; 90 (09) 1069-1077
- 52 Eves EM, Shapiro P, Naik K, Klein UR, Trakul N, Rosner MR. Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Mol Cell 2006; 23 (04) 561-574
- 53 Odabaei G, Chatterjee D, Jazirehi AR, Goodglick L, Yeung K, Bonavida B. Raf-1 kinase inhibitor protein: structure, function, regulation of cell signaling, and pivotal role in apoptosis. Adv Cancer Res 2004; 91: 169-200
- 54 Huerta-Yepez S, Vega M, Jazirehi A. , et al. Nitric oxide sensitizes prostate carcinoma cell lines to TRAIL-mediated apoptosis via inactivation of NF-kappa B and inhibition of Bcl-xl expression. Oncogene 2004; 23 (29) 4993-5003
- 55 Tsai MF, Wang CC, Chang GC. , et al. A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma. J Natl Cancer Inst 2006; 98 (12) 825-838
- 56 Wang CC, Tsai MF, Hong TM. , et al. The transcriptional factor YY1 upregulates the novel invasion suppressor HLJ1 expression and inhibits cancer cell invasion. Oncogene 2005; 24 (25) 4081-4093
- 57 Wang CC, Tsai MF, Dai TH. , et al. Synergistic activation of the tumor suppressor, HLJ1, by the transcription factors YY1 and activator protein 1. Cancer Res 2007; 67 (10) 4816-4826
- 58 Zhang L, Cai X, Chen K. , et al. Hepatitis B virus protein up-regulated HLJ1 expression via the transcription factor YY1 in human hepatocarcinoma cells. Virus Res 2011; 157 (01) 76-81
- 59 Benn J, Su F, Doria M, Schneider RJ. Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases. J Virol 1996; 70 (08) 4978-4985
- 60 Austen M, Cerni C, Lüscher-Firzlaff JM, Lüscher B. YY1 can inhibit c-Myc function through a mechanism requiring DNA binding of YY1 but neither its transactivation domain nor direct interaction with c-Myc. Oncogene 1998; 17 (04) 511-520
- 61 Bannasch P. Glycogenotic hepatocellular carcinoma with glycogen-ground-glass hepatocytes: a heuristically highly relevant phenotype. World J Gastroenterol 2012; 18 (46) 6701-6708
- 62 Huang Q, Tan Y, Yin P. , et al. Metabolic characterization of hepatocellular carcinoma using nontargeted tissue metabolomics. Cancer Res 2013; 73 (16) 4992-5002
- 63 Toshkov I, Chisari FV, Bannasch P. Hepatic preneoplasia in hepatitis B virus transgenic mice. Hepatology 1994; 20 (05) 1162-1172
- 64 Cornu M, Albert V, Hall MN. mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev 2013; 23 (01) 53-62
- 65 Yang JC, Teng CF, Wu HC. , et al. Enhanced expression of vascular endothelial growth factor-A in ground glass hepatocytes and its implication in hepatitis B virus hepatocarcinogenesis. Hepatology 2009; 49 (06) 1962-1971
- 66 Su IJ, Wang LH, Hsieh WC. , et al. The emerging role of hepatitis B virus pre-S2 deletion mutant proteins in HBV tumorigenesis. J Biomed Sci 2014; 21: 98
- 67 Teng CF, Wu HC, Shyu WC, Jeng LB, Su IJ. Pre-S2 mutant-induced mammalian target of rapamycin signal pathways as potential therapeutic targets for hepatitis B virus-associated hepatocellular carcinoma. Cell Transplant 2017; 26 (03) 429-438
- 68 Teng CF, Wu HC, Tsai HW, Shiah HS, Huang W, Su IJ. Novel feedback inhibition of surface antigen synthesis by mammalian target of rapamycin (mTOR) signal and its implication for hepatitis B virus tumorigenesis and therapy. Hepatology 2011; 54 (04) 1199-1207
- 69 Teng CF, Hsieh WC, Wu HC. , et al. Hepatitis B virus Pre-S2 mutant induces aerobic glycolysis through mammalian target of rapamycin signal cascade. PLoS One 2015; 10 (04) e0122373
- 70 Gnanaprakasam JNR, Sherman JW, Wang R. MYC and HIF in shaping immune response and immune metabolism. Cytokine Growth Factor Rev 2017; 35: 63-70
- 71 Amann T, Hellerbrand C. GLUT1 as a therapeutic target in hepatocellular carcinoma. Expert Opin Ther Targets 2009; 13 (12) 1411-1427
- 72 Legry V, Schaap FG, Delire B, Horsmans Y, Leclercq IA. Yin Yang 1 and farnesoid X receptor: a balancing act in non-alcoholic fatty liver disease?. Gut 2014; 63 (01) 1-2
- 73 Lu Y, Ma Z, Zhang Z. , et al. Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice. Gut 2014; 63 (01) 170-178
- 74 Preidis GA, Kim KH, Moore DD. Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance. J Clin Invest 2017; 127 (04) 1193-1201
- 75 Huang HY, Li X, Liu M. , et al. Transcription factor YY1 promotes adipogenesis via inhibiting CHOP-10 expression. Biochem Biophys Res Commun 2008; 375 (04) 496-500
- 76 Schlegel A. Studying non-alcoholic fatty liver disease with zebrafish: a confluence of optics, genetics, and physiology. Cell Mol Life Sci 2012; 69 (23) 3953-3961
- 77 Altamirano J, Bataller R. Alcoholic liver disease: pathogenesis and new targets for therapy. Nat Rev Gastroenterol Hepatol 2011; 8 (09) 491-501
- 78 Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011; 141 (05) 1572-1585
- 79 Tam J, Liu J, Mukhopadhyay B, Cinar R, Godlewski G, Kunos G. Endocannabinoids in liver disease. Hepatology 2011; 53 (01) 346-355
- 80 Miller LK, Devi LA. The highs and lows of cannabinoid receptor expression in disease: mechanisms and their therapeutic implications. Pharmacol Rev 2011; 63 (03) 461-470
- 81 Chanda D, Kim YH, Li T. , et al. Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. PLoS One 2013; 8 (07) e68845
- 82 Winkler GS. The mammalian anti-proliferative BTG/Tob protein family. J Cell Physiol 2010; 222 (01) 66-72
- 83 Hwang SL, Kwon O, Kim SG, Lee IK, Kim YD. B-cell translocation gene 2 positively regulates GLP-1-stimulated insulin secretion via induction of PDX-1 in pancreatic β-cells. Exp Mol Med 2013; 45: e25
- 84 Lee SE, Hwang SL, Jang WG, Chang HW, Kim YD. B-cell translocation gene 2 promotes hepatic hepcidin production via induction of Yin Yang 1. Biochem Biophys Res Commun 2015; 460 (04) 996-1001
- 85 Kim YD, Hwang SL, Lee EJ. , et al. Melatonin ameliorates alcohol-induced bile acid synthesis by enhancing miR-497 expression. J Pineal Res 2017; 62: e12386
- 86 Jedlitschky G, Hoffmann U, Kroemer HK. Structure and function of the MRP2 (ABCC2) protein and its role in drug disposition. Expert Opin Drug Metab Toxicol 2006; 2 (03) 351-366
- 87 Grube M, Meyer Zu Schwabedissen H, Draber K. , et al. Expression, localization, and function of the carnitine transporter octn2 (slc22a5) in human placenta. Drug Metab Dispos 2005; 33 (01) 31-37
- 88 Zollner G, Fickert P, Zenz R. , et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 2001; 33 (03) 633-646
- 89 Shoda J, Kano M, Oda K. , et al. The expression levels of plasma membrane transporters in the cholestatic liver of patients undergoing biliary drainage and their association with the impairment of biliary secretory function. Am J Gastroenterol 2001; 96 (12) 3368-3378
- 90 Chen HL, Liu YJ, Chen HL. , et al. Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia. Pediatr Res 2008; 63 (06) 667-673
- 91 Halilbasic E, Claudel T, Trauner M. Bile acid transporters and regulatory nuclear receptors in the liver and beyond. J Hepatol 2013; 58 (01) 155-168
- 92 Liu XC, Lian W, Zhang LJ. , et al. Interleukin-18 down-regulates multidrug resistance-associated protein 2 expression through farnesoid x receptor associated with nuclear factor kappa B and Yin Yang 1 in human hepatoma HepG2 cells. PLoS One 2015; 10 (08) e0136215
- 93 Her GM, Pai WY, Lai CY, Hsieh YW, Pang HW. Ubiquitous transcription factor YY1 promotes zebrafish liver steatosis and lipotoxicity by inhibiting CHOP-10 expression. Biochim Biophys Acta 2013; 1831 (06) 1037-1051
- 94 Yakovleva T, Kolesnikova L, Vukojević V. , et al. YY1 binding to a subset of p53 DNA-target sites regulates p53-dependent transcription. Biochem Biophys Res Commun 2004; 318 (02) 615-624
- 95 Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. Int J Cancer 2012; 130 (08) 1715-1725
- 96 Wan M, Huang W, Kute TE. , et al. Yin Yang 1 plays an essential role in breast cancer and negatively regulates p27. Am J Pathol 2012; 180 (05) 2120-2133
- 97 He G, Wang Q, Zhou Y. , et al. YY1 is a novel potential therapeutic target for the treatment of HPV infection-induced cervical cancer by arsenic trioxide. Int J Gynecol Cancer 2011; 21 (06) 1097-1104
- 98 Donia M, Maksimovic-Ivanic D, Mijatovic S. , et al. In vitro and in vivo anticancer action of Saquinavir-NO, a novel nitric oxide-derivative of the protease inhibitor saquinavir, on hormone resistant prostate cancer cells. Cell Cycle 2011; 10 (03) 492-499
- 99 Vega MI, Huerta-Yepez S, Jazirehi AR, Garban H, Bonavida B. Rituximab (chimeric anti-CD20) sensitizes B-NHL cell lines to Fas-induced apoptosis. Oncogene 2005; 24 (55) 8114-8127
- 100 Wilkinson FH, Park K, Atchison ML. Polycomb recruitment to DNA in vivo by the YY1 REPO domain. Proc Natl Acad Sci U S A 2006; 103 (51) 19296-19301