Epigenetic high regulation of ATAD2 regulates the Hh pathway in human hepatocellular carcinoma

Wu,Gang; Lu,Xiaojun; Wang,Yawei; He,Hui; Meng,Xiangyu; Xia,Shuguan; Zhen,Kunming; Liu,Yongfeng

doi:10.3892/ijo.2014.2416

Epigenetic high regulation of ATAD2 regulates the Hh pathway in human hepatocellular carcinoma

Authors:
- Gang Wu
- Xiaojun Lu
- Yawei Wang
- Hui He
- Xiangyu Meng
- Shuguan Xia
- Kunming Zhen
- Yongfeng Liu
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Affiliations: Department of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
Published online on: May 6, 2014 https://doi.org/10.3892/ijo.2014.2416
Pages: 351-361

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Abstract

ATAD2 is associated with many cellular progresses such as cell growth, differentiation and apoptosis. Some studies suggest ATAD2 is highly expressed in cancer cells. In our previous studies, we found that ATAD2 is highly expressed in HCC tissues, compared with adjacent normal tissues, and patients with high expression of ATAD2 had a poorer prognosis. Moreover, we found mir-372 can regulate the expression of ATAD2 in HCC cell lines. We also detected a relationship between the mRNA expression of ATAD2 and Ptch1 by gene microarray. Here, we completed the function studies of ATAD2 in vivo and in vitro, and tested whether ATAD2 could regulate the Hh pathway. ATAD2 and Hh pathway protein expressions in 80 HCC specimens were examined by immunohistochemistry (IHC). The mRNA expression of ATAD2 and Hh pathway members in paired-HCC tissues and cell lines were, respectively, analyzed using quantitative PCR. ATAD2‑RNAi was transduced into HCCLM3 and Huh7 cells, using a lentiviral vector. The effect of ATAD2 in HCC cell lines on cell cycle and apoptosis were evaluated by flow cytometry. Tumorigenicity experiments in nude mice were performed to test the function of ATAD2 in vivo. Pharmacological regulation of Hh signaling was performed to test the relation between the ATAD2 and Hh pathways and C-myc. We found that ATAD2 and Ptch1 were both highly expressed in HCC tissues, compared with paired normal hepatic tissues. In addition, we found that ATAD2 could affect the expression of the Hh pathway by PCR and western blot anaysis in HCC cell lines, by observing the outcome before and after transfection. We speculate that ATAD2 cooperates with the MYC gene to regulate the expression of SMO and Gli, activating the Hh pathway and inducing an active feedback of the Hh pathway.

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1.	But DY, Lai CL and Yuen MF: Natural history of hepatitis-related hepatocellular carcinoma. World J Gastroenterol. 14:1652–1656. 2008. View Article : Google Scholar : PubMed/NCBI
2.	Chen HW, et al: Expression of FOXJ1 in hepatocellular carcinoma: Correlation with patients’ prognosis and tumor cell proliferation. Mol Carcinog. 52:647–659. 2013.PubMed/NCBI
3.	He H, Wu G, Li W, Cao Y and Liu Y: CIP2A is highly expressed in hepatocellular carcinoma and predicts poor prognosis. Diagn Mol Pathol. 21:143–149. 2012. View Article : Google Scholar : PubMed/NCBI
4.	Block TM, Mehta AS, Fimmel CJ and Jordan R: Molecular viral oncology of hepatocellular carcinoma. Oncogene. 22:5093–5107. 2003. View Article : Google Scholar : PubMed/NCBI
5.	Feng JT, Shang S and Beretta L: Proteomics for the early detection and treatment of hepatocellular carcinoma. Oncogene. 25:3810–3817. 2006. View Article : Google Scholar
6.	Zou JX, Revenko AS, Li LB, et al: ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERalpha, is required for coregulator occupancy and chromatin modification. Proc Natl Acad Sci USA. 104:18067–18072. 2007.PubMed/NCBI
7.	Ciró M, Prosperini E, Quarto M, et al: ATAD2 is a novel cofactor for MYC, overexpressed and amplified in aggressive tumors. Cancer Res. 69:8491–8498. 2009.PubMed/NCBI
8.	Alizadeh AA, Eisen MB, Davis RE, et al: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 403:503–511. 2000. View Article : Google Scholar : PubMed/NCBI
9.	Chen X, Cheung ST, So S, et al: Gene expression patterns in human liver cancers. Mol Biol Cell. 13:1929–1939. 2002. View Article : Google Scholar PubMed/NCBI
10.	Ma XJ, Salunga R, Tuggle JT, et al: Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci USA. 100:5974–5979. 2003. View Article : Google Scholar : PubMed/NCBI
11.	Huang Q, Lin B, Liu H, et al: RNA-Seq analyses generate comprehensive transcriptomic landscape and reveal complex transcript patterns in hepatocellular carcinoma. PLoS One. 6:e261682011. View Article : Google Scholar
12.	Cheng WT, Xu K, Tian DY, et al: Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells. Int J Oncol. 34:829–836. 2009.PubMed/NCBI
13.	Sicklick JK, Li YX, Jayaraman A, et al: Dysregulation of the hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis. 27:748–757. 2006. View Article : Google Scholar : PubMed/NCBI
14.	Patil MA, Zhang J, Ho C, et al: Hedgehog signaling in human hepatocellular carcinoma. Cancer Biol Ther. 5:111–117. 2006. View Article : Google Scholar : PubMed/NCBI
15.	Ruiz i Altaba A, Sánchez P and Dahmane N: Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2:361–372. 2002.PubMed/NCBI
16.	Ingham PW and McMahon AP: Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15:3059–3087. 2001. View Article : Google Scholar : PubMed/NCBI
17.	Cohen MM Jr: The Hedgehog signaling network. Am J Med Genet A. 123A:5–28. 2003. View Article : Google Scholar : PubMed/NCBI
18.	Wu G, Liu H, He H, Wang Y, Lu X, et al: miR-372 down-regulates the oncogene ATAD2 to influence hepatocellular carcinoma proliferation and metastasis. BMC Cancer. 14:1072014. View Article : Google Scholar : PubMed/NCBI
19.	Pivot-Pajot C, Caron C, Govin J, et al: Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromo-domain-containing protein. Mol Cell Biol. 23:5354–5365. 2003. View Article : Google Scholar : PubMed/NCBI
20.	Filippakopoulos P, Picaud S, Mangos M, et al: Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 149:214–231. 2012. View Article : Google Scholar : PubMed/NCBI
21.	Caron C, Lestrat C, Marsal S, et al: Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers. Oncogene. 29:5171–5181. 2010. View Article : Google Scholar : PubMed/NCBI
22.	Seoane J, Pouponnot C, Staller P, Schader M, Eilers M, et al: TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat Cell Biol. 3:400–408. 2001. View Article : Google Scholar : PubMed/NCBI
23.	Leachman NT, Brellier F, Ferralli J, et al: ATAD2B is a phylogenetically conserved nuclear protein expressed during neuronal differentiation and tumorigenesis. Dev Growth Differ. 52:747–755. 2010. View Article : Google Scholar : PubMed/NCBI
24.	Lu J, Chen M, Ren XR, et al: Regulation of Hedgehog signaling by Myc-interacting zinc finger protein 1, Miz1. PLoS One. 8:e633532013. View Article : Google Scholar : PubMed/NCBI
25.	Peukert K, Staller P, Schneider A, et al: An alternative pathway for gene regulation by Myc. EMBO J. 16:5672–5686. 1997. View Article : Google Scholar : PubMed/NCBI
26.	Wanzel M, Herold S and Eilers M: Transcriptional repression by Myc. Trends Cell Biol. 13:146–150. 2003. View Article : Google Scholar : PubMed/NCBI
27.	Patel JH and McMahon SB: BCL2 is a downstream effector of MIZ-1 essential for blocking c-MYC-induced apoptosis. J Biol Chem. 282:5–13. 2007. View Article : Google Scholar : PubMed/NCBI
28.	Rao G, Pedone CA, Coffin CM, Holland EC and Fults DW: c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice. Neoplasia. 5:198–204. 2003. View Article : Google Scholar : PubMed/NCBI
29.	Wang Y, Wu MC, Sham JS, et al: Prognostic significance of c-myc and AIB1 amplification in hepatocellular carcinoma. A broad survey using high-throughput tissue microarray. Cancer. 95:2346–2352. 2002. View Article : Google Scholar : PubMed/NCBI
30.	Shachaf CM, Kopelman AM, Arvanitis C, et al: MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 431:1112–1117. 2004. View Article : Google Scholar : PubMed/NCBI