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Yin Yang-1 suppresses differentiation of hepatocellular carcinoma cells through the downregulation of CCAAT/enhancer-binding protein alpha

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Abstract

As a member of the GLI-Kruppel family of transcriptional factors, Yin Yang-1 (YY1) functions as an oncogene in various types of cancers. However, the role of YY1 in hepatocellular carcinogenesis remains unknown. In this report, we investigated the relevance of YY1 to hepatocellular carcinoma (HCC) development. We found that YY1 was upregulated in HCC cell lines. Ectopic YY1 expression promoted the growth of non-tumor liver cells that expressed low level of YY1. In contrast, YY1 depletion inhibited the growth of HCC cells which was accompanied with distinct morphological changes. Moreover, the phenotypic changes induced by YY1 depletion were attributed to cellular differentiation rather than cellular senescence. CCAAT/enhancer-binding protein alpha (CEBPA) which was important to regulate differentiation of hepatocytes was found as the direct target downregulated by YY1. Restoration of CEBPA in YY1-expressing HCC cells induced cellular differentiation and growth inhibition while knockdown of CEBPA expression in non-tumor liver cells promoted cell growth. In summary, our study demonstrated that YY1 could promote hepatocellular carcinogenesis and inhibit cellular differentiation through the downregulation of CEBPA expression.

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References

  1. El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576. doi:10.1053/j.gastro.2007.04.061

    Article  PubMed  CAS  Google Scholar 

  2. Seligson D, Horvath S, Huerta-Yepez S, Hanna S, Garban H, Roberts A, Shi T, Liu X, Chia D, Goodglick L et al (2005) Expression of transcription factor Yin Yang 1 in prostate cancer. Int J Oncol 27:131–141

    PubMed  CAS  Google Scholar 

  3. Matsumura N, Huang Z, Baba T, Lee PS, Barnett JC, Mori S, Chang JT, Kuo WL, Gusberg AH, Whitaker RS et al (2009) Yin yang 1 modulates taxane response in epithelial ovarian cancer. Mol Cancer Res 7:210–220. doi:10.1158/1541-7786.MCR-08-0255

    Article  PubMed  CAS  Google Scholar 

  4. Chinnappan D, Xiao D, Ratnasari A, Andry C, King TC, Weber HC (2009) Transcription factor YY1 expression in human gastrointestinal cancer cells. Int J Oncol 34:1417–1423

    PubMed  CAS  Google Scholar 

  5. Kim J (2009) YY1's longer DNA-binding motifs. Genomics 93:152–158. doi:10.1016/j.ygeno.2008.09.013

    Article  PubMed  CAS  Google Scholar 

  6. Castellano G, Torrisi E, Ligresti G, Malaponte G, Militello L, Russo AE, McCubrey JA, Canevari S, Libra M (2009) The involvement of the transcription factor Yin Yang 1 in cancer development and progression. Cell Cycle 8:1367–1372

    Article  PubMed  CAS  Google Scholar 

  7. Gordon S, Akopyan G, Garban H, Bonavida B (2006) Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene 25:1125–1142. doi:10.1038/sj.onc.1209080

    Article  PubMed  CAS  Google Scholar 

  8. Tong ZT, Cai MY, Wang XG, Kong LL, Mai SJ, Liu YH, Zhang HB, Liao YJ, Zheng F, Zhu W et al (2011) EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. Oncogene. doi:10.1038/onc.2011.254

  9. de Nigris F, Crudele V, Giovane A, Casamassimi A, Giordano A, Garban HJ, Cacciatore F, Pentimalli F, Marquez-Garban DC, Petrillo A et al (2010) CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy. Proc Natl Acad Sci U S A 107:14484–14489. doi:10.1073/pnas.1008256107

    Article  PubMed  Google Scholar 

  10. Gronroos E, Terentiev AA, Punga T, Ericsson J (2004) YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proc Natl Acad Sci U S A 101:12165–12170. doi:10.1073/pnas.0402283101

    Article  PubMed  Google Scholar 

  11. Begon DY, Delacroix L, Vernimmen D, Jackers P, Winkler R (2005) Yin Yang 1 cooperates with activator protein 2 to stimulate ERBB2 gene expression in mammary cancer cells. J Biol Chem 280:24428–24434. doi:10.1074/jbc.M503790200

    Article  PubMed  CAS  Google Scholar 

  12. Lee MH, Lahusen T, Wang RH, Xiao C, Xu X, Hwang YS, He WW, Shi Y, Deng CX (2011) Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation. Oncogene. doi:10.1038/onc.2011.217

  13. Austen M, Cerni C, Luscher-Firzlaff JM, Luscher B (1998) 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 17:511–520. doi:10.1038/sj.onc.1201968

    Article  PubMed  CAS  Google Scholar 

  14. Wang CC, Tsai MF, Dai TH, Hong TM, Chan WK, Chen JJ, Yang PC (2007) Synergistic activation of the tumor suppressor, HLJ1, by the transcription factors YY1 and activator protein 1. Cancer Res 67:4816–4826. doi:10.1158/0008-5472.CAN-07-0504

    Article  PubMed  CAS  Google Scholar 

  15. Wang H, Hertlein E, Bakkar N, Sun H, Acharyya S, Wang J, Carathers M, Davuluri R, Guttridge DC (2007) NF-kappaB regulation of YY1 inhibits skeletal myogenesis through transcriptional silencing of myofibrillar genes. Mol Cell Biol 27:4374–4387. doi:10.1128/MCB.02020-06

    Article  PubMed  CAS  Google Scholar 

  16. Wang H, Garzon R, Sun H, Ladner KJ, Singh R, Dahlman J, Cheng A, Hall BM, Qualman SJ, Chandler DS et al (2008) NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell 14:369–381. doi:10.1016/j.ccr.2008.10.006

    Article  PubMed  CAS  Google Scholar 

  17. Schuster MB, Porse BT (2006) C/EBPalpha: a tumour suppressor in multiple tissues? Biochim Biophys Acta 1766:88–103. doi:10.1016/j.bbcan.2006.02.003

    PubMed  CAS  Google Scholar 

  18. Tan EH, Hooi SC, Laban M, Wong E, Ponniah S, Wee A, Wang ND (2005) CCAAT/enhancer binding protein alpha knock-in mice exhibit early liver glycogen storage and reduced susceptibility to hepatocellular carcinoma. Cancer Res 65:10330–10337. doi:10.1158/0008-5472.CAN-04-4486

    Article  PubMed  CAS  Google Scholar 

  19. Tseng HH, Hwang YH, Yeh KT, Chang JG, Chen YL, Yu HS (2009) Reduced expression of C/EBP alpha protein in hepatocellular carcinoma is associated with advanced tumor stage and shortened patient survival. J Cancer Res Clin Oncol 135:241–247. doi:10.1007/s00432-008-0448-5

    Article  PubMed  CAS  Google Scholar 

  20. Zeng C, Wang R, Li D, Lin XJ, Wei QK, Yuan Y, Wang Q, Chen W, Zhuang SM (2010) A novel GSK-3 beta-C/EBP alpha-miR-122-insulin-like growth factor 1 receptor regulatory circuitry in human hepatocellular carcinoma. Hepatology 52:1702–1712. doi:10.1002/hep.23875

    Article  PubMed  CAS  Google Scholar 

  21. Ko CY, Hsu HC, Shen MR, Chang WC, Wang JM (2008) Epigenetic silencing of CCAAT/enhancer-binding protein delta activity by YY1/polycomb group/DNA methyltransferase complex. J Biol Chem 283:30919–30932. doi:10.1074/jbc.M804029200

    Article  PubMed  CAS  Google Scholar 

  22. Lin TC, Hou HA, Chou WC, Ou DL, Yu SL, Tien HF, Lin LI (2011) CEBPA methylation as a prognostic biomarker in patients with de novo acute myeloid leukemia. Leukemia 25:32–40. doi:10.1038/leu.2010.222

    Article  PubMed  CAS  Google Scholar 

  23. Kumagai T, Akagi T, Desmond JC, Kawamata N, Gery S, Imai Y, Song JH, Gui D, Said J, Koeffler HP (2009) Epigenetic regulation and molecular characterization of C/EBPalpha in pancreatic cancer cells. Int J Cancer 124:827–833. doi:10.1002/ijc.23994

    Article  PubMed  CAS  Google Scholar 

  24. Bennett KL, Romigh T, Arab K, Teresi RE, Tada Y, Eng C, Plass C (2009) Activator protein 2 alpha (AP2alpha) suppresses 42 kDa C/CAAT enhancer binding protein alpha (p42(C/EBPalpha)) in head and neck squamous cell carcinoma. Int J Cancer 124:1285–1292. doi:10.1002/ijc.24087

    Article  PubMed  CAS  Google Scholar 

  25. Tada Y, Brena RM, Hackanson B, Morrison C, Otterson GA, Plass C (2006) Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein alpha activity in lung cancer. J Natl Cancer Inst 98:396–406. doi:10.1093/jnci/djj093

    Article  PubMed  CAS  Google Scholar 

  26. Samarakoon R, Higgins PJ (2008) Integration of non-SMAD and SMAD signaling in TGF-beta1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells. Thromb Haemost 100:976–983

    PubMed  CAS  Google Scholar 

  27. Teng CF, Wu HC, Tsai HW, Shiah HS, Huang W, Su IJ (2011) 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 54:1199–1207. doi:10.1002/hep.24529

    Article  PubMed  CAS  Google Scholar 

  28. Zhang L, Cai X, Chen K, Wang Z, Wang L, Ren M, Huang A, Tang H (2011) Hepatitis B virus protein up-regulated HLJ1 expression via the transcription factor YY1 in human hepatocarcinoma cells. Virus Res 157:76–81. doi:10.1016/j.virusres.2011.02.009

    Article  PubMed  CAS  Google Scholar 

  29. Lam EK, Wang X, Shin VY, Zhang S, Morrison H, Sun J, Ng EK, Yu J, Jin H (2011) A microRNA contribution to aberrant Ras activation in gastric cancer. Am J Transl Res 3:209–218

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Program for Innovative Research Team in Zhejiang Province (grant no. 2010R50046), Natural Science Foundation of Zhejiang Province to LF (grant no. Y2110257) and Program for New Century Excellent Talents in University to HJ.

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Authors and Affiliations

  1. Laboratory of Cancer Epigenetics, Key Laboratory of Biotherapy in Zhejiang Province, Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Shengjie Zhang, Tingting Jiang, Lifeng Feng, Jie Sun, Haiqi Lu, Qinchuan Wang, Min Pan, Xian Wang & Hongchuan Jin

  2. Department of Surgical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Shengjie Zhang, Qinchuan Wang & Linbo Wang

  3. Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Dongsheng Huang

Authors
  1. Shengjie Zhang
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  2. Tingting Jiang
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  3. Lifeng Feng
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  4. Jie Sun
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  9. Xian Wang
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  10. Linbo Wang
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  11. Hongchuan Jin
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Corresponding authors

Correspondence to Linbo Wang or Hongchuan Jin.

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Shengjie Zhang and Tingting Jiang contribute to the work equally.

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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 90, 1069–1077 (2012). https://doi.org/10.1007/s00109-012-0879-y

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  • DOI: https://doi.org/10.1007/s00109-012-0879-y

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