Nordihydroguaiaretic acid inhibits growth of cervical cancer SiHa cells by up-regulating p21

Gao,Peng; Zhai,Fei; Guan,Lei; Zheng,Jie

doi:10.3892/ol.2010.205

Nordihydroguaiaretic acid inhibits growth of cervical cancer SiHa cells by up-regulating p21

Authors:
- Peng Gao
- Fei Zhai
- Lei Guan
- Jie Zheng
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Affiliations: Department of Pathology and Pathophysiology, School of Medical Science, Southeast University, Nanjing, Jiangsu 210009, P.R. China
Published online on: November 10, 2010 https://doi.org/10.3892/ol.2010.205
Pages: 123-128

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Abstract

Nordihydroguaiaretic acid (NDGA) and its derivatives possess anti-cancer effects on various types of cancer via the induction of apoptosis or cell cycle arrest. This study proved that NDGA inhibited cervical cancer SiHa cell growth and induced cell cycle arrest at the G1 phase, which may be a consequence of cell cycle kinase inhibitor p21 induction. NDGA promoted acetylation of histone H3 in total and p21 gene-associated chromatin. This effect is gene selective, since NDGA has no impact on the p27 gene. NDGA also inhibited HPV-16 E6 gene transcription, which in turn resulted in the restoration of p53 protein levels. The silencing mediator for retinoid and thyroid hormone receptors (SMRT) is a key component of the HDAC3-HDAC4-N-CoR/SMRT complex. We found that NDGA significantly inhibited the transcription of SMRT, which, together with p53, may aid in the detection of the increase of histone H3 acetylation within the p21 gene. Our results suggest that NDGA induces p21 transcription by selectively elevating histone H3 acetylation associated with p21 gene and p53 protein levels via the inhibition of HPV-16 E6 expression.

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1	Allen KL, Tschantz DR, Awad KS, Lynch WP and DeLucia AL: A plant lignan, 3′-O-methyl-nordihydroguaiaretic acid, suppresses papillomavirus E6 protein function, stabilizes p53 protein, and induces apoptosis in cervical tumor cells. Mol Carcinog. 46:564–575. 2007.
2	Meyer GE, Chesler L, Liu D, Gable K, Maddux BA, Goldenberg DD, Youngren JF, Goldfine ID, Weiss WA, Matthay KK and Rosenthal SM: Nordihydroguaiaretic acid inhibits insulin-like growth factor signaling, growth, and survival in human neuroblastoma cells. J Cell Biochem. 102:1529–1541. 2007. View Article : Google Scholar : PubMed/NCBI
3	Meyers RO, Lambert JD, Hajicek N, Pourpak A, Kalaitzis JA and Dorr RT: Synthesis, characterization, and anti-melanoma activity of tetra-O-substituted analogs of nordihydroguaiaretic acid. Bioorg Med Chem Lett. 19:4752–4755. 2009. View Article : Google Scholar : PubMed/NCBI
4	Zur Hausen H: Papillomavirus infections – a major cause of human cancers. Biochim Biophys Acta. 1288:F55–F78. 1996.
5	Narisawa-Saito M and Kiyono T: Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: roles of E6 and E7 proteins. Cancer Sci. 98:1505–1511. 2007. View Article : Google Scholar : PubMed/NCBI
6	Zhao J, Zhao Y, Chen W, Li YM and Bian XW: The differentiation- inducing effect of Nordy on HPV-16 subgenes-immortalized human endocervical cells H8. Anticancer Drugs. 19:713–719. 2008. View Article : Google Scholar
7	Bahnassy AA, Zekri AR, Alam El-Din HM, Aboubakr AA, Kamel K, El-Sabah MT and Mokhtar NM: The role of cyclins and cyclins inhibitors in the multistep process of HPV-associated cervical carcinoma. J Egypt Natl Canc Inst. 18:292–302. 2006.PubMed/NCBI
8	Tsao YP, Huang SJ, Chang JL, Hsieh JT, Pong RC and Chen SL: Adenovirus-mediated p21(WAF1/SDII/CIP1) gene transfer induces apoptosis of human cervical cancer cell lines. J Virol. 73:4983–4990. 1999.PubMed/NCBI
9	Hirano K, Hirano M, Zeng Y, Nishimura J, Hara K, Muta K, Nawata H and Kanaide H: Cloning and functional expression of a degradation-resistant novel isoform of p27Kip1. Biochem J. 353:51–57. 2001. View Article : Google Scholar : PubMed/NCBI
10	Abbas T and Dutta A: p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 9:400–414. 2009. View Article : Google Scholar : PubMed/NCBI
11	Chen YX, Fang JY, Lu R and Qiu DK: Expression of p21(WAF1) is related to acetylation of histone H3 in total chromatin in human colorectal cancer. World J Gastroenterol. 13:2209–2213. 2007. View Article : Google Scholar : PubMed/NCBI
12	Richon VM, Sandhoff TW, Rifkind RA and Marks PA: Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA. 97:10014–10019. 2000. View Article : Google Scholar : PubMed/NCBI
13	Giannoudis A and Herrington CS: Differential expression of p53 and p21 in low grade cervical squamous intraepithelial lesions infected with low, intermediate, and high risk human papillomaviruses. Cancer. 89:1300–1307. 2000. View Article : Google Scholar
14	Hietanen S, Lain S, Krausz E, Blattner C and Lane DP: Activation of p53 in cervical carcinoma cells by small molecules. Proc Natl Acad Sci USA. 97:8501–8506. 2000. View Article : Google Scholar : PubMed/NCBI
15	De-Castro Arce J, Göckel-Krzikalla E and Rösl F: Retinoic acid receptor beta silences human papillomavirus-18 oncogene expression by induction of de novo methylation and heterochromatinization of the viral control region. J Biol Chem. 282:28520–28529. 2007.PubMed/NCBI
16	Deng Y, Lin C, Zheng J, Fu M, Liang X, Chen J, Xiao P and Wu M: Overexpression of Bcl-2 partly inhibits apoptosis of human cervical cancer SiHa cells induced by arsenic trioxide. Chin Med J (In English). 113:84–88. 2000.PubMed/NCBI
17	Yoshinouchi M, Yamada T, Kizaki M, Fen J, Koseki T, Ikeda Y, Nishihara T and Yamato K: In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by E6 siRNA. Mol Ther. 8:762–768. 2003. View Article : Google Scholar : PubMed/NCBI
18	Lagger G, Doetzlhofer A, Schuettengruber B, Haidweger E, Simboeck E, Tischler J, Chiocca S, Suske G, Rotheneder H, Wintersberger E and Seiser C: The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 gene. Mol Cell Biol. 23:2669–2679. 2003. View Article : Google Scholar : PubMed/NCBI
19	Allison SJ, Jiang M and Milner J: Oncogenic viral protein HPV E7 up-regulates the SIRT1 longevity protein in human cervical cancer cells. Aging. 1:316–327. 2009.PubMed/NCBI
20	Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L and Weinberg RA: hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 107:149–159. 2001. View Article : Google Scholar : PubMed/NCBI
21	Yamakuchi M, Ferlito M and Lowenstein CJ: miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci USA. 105:13421–13426. 2008. View Article : Google Scholar : PubMed/NCBI
22	Jenuwein T and Allis CD: Translating the histone code. Science. 293:1074–1080. 2001. View Article : Google Scholar : PubMed/NCBI
23	Allison SJ and Milner J: Loss of p53 has site-specific effects on histone H3 modification, including serine 10 phosphorylation important for maintenance of ploidy. Cancer Res. 63:6674–6679. 2003.PubMed/NCBI
24	Warnock LJ, Adamson R, Lynch CJ and Milner J: Crosstalk between site-specific modifications on p53 and histone H3. Oncogene. 27:1639–1644. 2008. View Article : Google Scholar : PubMed/NCBI
25	Eberharter A and Becker PB: Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Rep. 3:224–229. 2002. View Article : Google Scholar : PubMed/NCBI
26	Xiao H, Hasegawa T and Isobe K: p300 collaborates with Sp1 and Sp3 in p21(waf1/cip1) promoter activation induced by histone deacetylase inhibitor. J Biol Chem. 275:1371–1376. 2000. View Article : Google Scholar : PubMed/NCBI
27	Ohshima T, Suganuma T and Ikeda M: A novel mutation lacking the bromodomain of the transcriptional coactivator p300 in the SiHa cervical carcinoma cell line. Biochem Biophys Res Commun. 281:569–575. 2001. View Article : Google Scholar : PubMed/NCBI
28	Wilson AJ, Byun DS, Nasser S, Murray LB, Ayyanar K, Arango D, Figueroa M, Melnick A, Kao GD, Augenlicht LH and Mariadason JM: HDAC4 promotes growth of colon cancer cells via repression of p21. Mol Biol Cell. 19:4062–4075. 2008. View Article : Google Scholar : PubMed/NCBI