Epigenetic regulation of proliferation and invasion in hepatocellular carcinoma cells by CBP/p300 histone acetyltransferase activity

  • Authors:
    • Yuji Inagaki
    • Katsuya Shiraki
    • Kazushi Sugimoto
    • Takazumi Yada
    • Masahiko Tameda
    • Suguru Ogura
    • Norihiko Yamamoto
    • Yoshiyuki Takei
    • Masaaki Ito
  • View Affiliations

  • Published online on: December 11, 2015     https://doi.org/10.3892/ijo.2015.3288
  • Pages: 533-540
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Abstract

Altered epigenetic control of gene expression plays a substantial role in tumor development and progression. Accumulating studies suggest that somatic mutations of CREB binding proteins (CBP)/p300 occur in some cancer cells. CBP/p300 possess histone acetyltransferase (HAT) activity, and are involved in many cellular processes. In this study, we investigated the expression and functional role of CBP/p300 in hepatocellular carcinoma (HCC) using the specific inhibitor C646 of CBP/p300 HAT activity. We examined its effect on several apoptosis-related proteins and invasion-related genes. The results showed that CBP/p300 were highly expressed in HCC tissues and that expression of p300, but not of CBP, was strongly correlated with the malignant character of HCC. C646 inhibited proliferation of HCC cell lines in a dose dependent manner. C646 significantly augmented TRAIL-induced apoptotic sensitivity, which was accompanied by reduced levels of survivin, in HepG2, HLE and SK-HEP1 cells. C646 significantly inhibited invasion of Huh7, HLE and SK-HEP1 cells. The level of matrix metallopeptidase 15 (MMP15) mRNA expression was significantly reduced, whereas the level of laminin alpha 3 (LAMA3) and secreted phosphoprotein 1 (SPP1) mRNA expression was significantly increased in Huh7 cells following exposure to C646. In conclusion, our results suggest that CBP/p300 HAT activity has an important role in malignant transformation, proliferation, apoptotic sensitivity and invasion in HCC. CBP/p300 could be a promising therapeutic target in HCC.

References

1 

Waldmann T and Schneider R: Targeting histone modifications - epigenetics in cancer. Curr Opin Cell Biol. 25:184–189. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Dawson MA, Kouzarides T and Huntly BJ: Targeting epigenetic readers in cancer. N Engl J Med. 367:647–657. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Dawson MA and Kouzarides T: Cancer epigenetics: From mechanism to therapy. Cell. 150:12–27. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Wang F, Marshall CB and Ikura M: Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: Structural and functional versatility in target recognition. Cell Mol Life Sci. 70:3989–4008. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Bedford DC, Kasper LH, Fukuyama T and Brindle PK: Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases. Epigenetics. 5:9–15. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Kalkhoven E: CBP and p300: HATs for different occasions. Biochem Pharmacol. 68:1145–1155. 2004. View Article : Google Scholar : PubMed/NCBI

7 

Borrow J, Stanton VP Jr, Andresen JM, Becher R, Behm FG, Chaganti RS, Civin CI, Disteche C, Dubé I, Frischauf AM, et al: The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet. 14:33–41. 1996. View Article : Google Scholar : PubMed/NCBI

8 

Chaffanet M, Gressin L, Preudhomme C, Soenen-Cornu V, Birnbaum D and Pébusque MJ: MOZ is fused to p300 in an acute monocytic leukemia with t(8;22). Genes Chromosomes Cancer. 28:138–144. 2000. View Article : Google Scholar : PubMed/NCBI

9 

Muraoka M, Konishi M, Kikuchi-Yanoshita R, Tanaka K, Shitara N, Chong JM, Iwama T and Miyaki M: p300 gene alterations in colorectal and gastric carcinomas. Oncogene. 12:1565–1569. 1996.PubMed/NCBI

10 

Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin SF, Daigo Y, Russell P, Wilson A, Sowter HM, et al: Mutations truncating the EP300 acetylase in human cancers. Nat Genet. 24:300–303. 2000. View Article : Google Scholar : PubMed/NCBI

11 

Kung AL, Rebel VI, Bronson RT, Ch'ng LE, Sieff CA, Livingston DM and Yao TP: Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev. 14:272–277. 2000.PubMed/NCBI

12 

Rebel VI, Kung AL, Tanner EA, Yang H, Bronson RT and Livingston DM: Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal. Proc Natl Acad Sci USA. 99:14789–14794. 2002. View Article : Google Scholar : PubMed/NCBI

13 

Ionov Y, Matsui S and Cowell JK: A role for p300/CREB binding protein genes in promoting cancer progression in colon cancer cell lines with microsatellite instability. Proc Natl Acad Sci USA. 101:1273–1278. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Iyer NG, Chin SF, Ozdag H, Daigo Y, Hu DE, Cariati M, Brindle K, Aparicio S and Caldas C: p300 regulates p53-dependent apoptosis after DNA damage in colorectal cancer cells by modulation of PUMA/p21 levels. Proc Natl Acad Sci USA. 101:7386–7391. 2004. View Article : Google Scholar : PubMed/NCBI

15 

Krubasik D, Iyer NG, English WR, Ahmed AA, Vias M, Roskelley C, Brenton JD, Caldas C and Murphy G: Absence of p300 induces cellular phenotypic changes characteristic of epithelial to mesenchyme transition. Br J Cancer. 94:1326–1332. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Ozen C, Yildiz G, Dagcan AT, Cevik D, Ors A, Keles U, Topel H and Ozturk M: Genetics and epigenetics of liver cancer. N Biotechnol. 30:381–384. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Pogribny IP and Rusyn I: Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma. Cancer Lett. 342:223–230. 2014. View Article : Google Scholar :

18 

Ma L, Chua MS, Andrisani O and So S: Epigenetics in hepatocellular carcinoma: An update and future therapy perspectives. World J Gastroenterol. 20:333–345. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Bowers EM, Yan G, Mukherjee C, Orry A, Wang L, Holbert MA, Crump NT, Hazzalin CA, Liszczak G, Yuan H, et al: Virtual ligand screening of the p300/CBP histone acetyltransferase: Identification of a selective small molecule inhibitor. Chem Biol. 17:471–482. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Santer FR, Höschele PP, Oh SJ, Erb HH, Bouchal J, Cavarretta IT, Parson W, Meyers DJ, Cole PA and Culig Z: Inhibition of the acetyltransferases p300 and CBP reveals a targetable function for p300 in the survival and invasion pathways of prostate cancer cell lines. Mol Cancer Ther. 10:1644–1655. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Yan G, Eller MS, Elm C, Larocca CA, Ryu B, Panova IP, Dancy BM, Bowers EM, Meyers D, Lareau L, et al: Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells. J Invest Dermatol. 133:2444–2452. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Oike T, Komachi M, Ogiwara H, Amornwichet N, Saitoh Y, Torikai K, Kubo N, Nakano T and Kohno T: C646, a selective small molecule inhibitor of histone acetyltransferase p300, radio-sensitizes lung cancer cells by enhancing mitotic catastrophe. Radiother Oncol. 111:222–227. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Gao XN, Lin J, Ning QY, Gao L, Yao YS, Zhou JH, Li YH, Wang LL and Yu L: A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells. PLoS One. 8:e554812013. View Article : Google Scholar : PubMed/NCBI

24 

Fuke H, Shiraki K, Sugimoto K, Tanaka J, Beppu T, Yoneda K, Yamamoto N, Ito K, Masuya M and Takei Y: Jak inhibitor induces S phase cell-cycle arrest and augments TRAIL-induced apoptosis in human hepatocellular carcinoma cells. Biochem Biophys Res Commun. 363:738–744. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Isharwal S, Miller MC, Marlow C, Makarov DV, Partin AW and Veltri RW: p300 (histone acetyltransferase) biomarker predicts prostate cancer biochemical recurrence and correlates with changes in epithelia nuclear size and shape. Prostate. 68:1097–1104. 2008. View Article : Google Scholar : PubMed/NCBI

26 

Ishihama K, Yamakawa M, Semba S, Takeda H, Kawata S, Kimura S and Kimura W: Expression of HDAC1 and CBP/p300 in human colorectal carcinomas. J Clin Pathol. 60:1205–1210. 2007. View Article : Google Scholar : PubMed/NCBI

27 

Liao ZW, Zhou TC, Tan XJ, Song XL, Liu Y, Shi XY, Huang WJ, Du LL, Tu BJ and Lin XD: High expression of p300 is linked to aggressive features and poor prognosis of nasopharyngeal carcinoma. J Transl Med. 10:1102012. View Article : Google Scholar : PubMed/NCBI

28 

Li M, Luo RZ, Chen JW, Cao Y, Lu JB, He JH, Wu QL and Cai MY: High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma. J Transl Med. 9:52011. View Article : Google Scholar : PubMed/NCBI

29 

Ito T, Shiraki K, Sugimoto K, Yamanaka T, Fujikawa K, Ito M, Takase K, Moriyama M, Kawano H, Hayashida M, et al: Survivin promotes cell proliferation in human hepatocellular carcinoma. Hepatology. 31:1080–1085. 2000. View Article : Google Scholar : PubMed/NCBI

30 

Takehara T, Liu X, Fujimoto J, Friedman SL and Takahashi H: Expression and role of Bcl-xL in human hepatocellular carcinomas. Hepatology. 34:55–61. 2001. View Article : Google Scholar : PubMed/NCBI

31 

Shiraki K, Sugimoto K, Yamanaka Y, Yamaguchi Y, Saitou Y, Ito K, Yamamoto N, Yamanaka T, Fujikawa K, Murata K, et al: Overexpression of X-linked inhibitor of apoptosis in human hepatocellular carcinoma. Int J Mol Med. 12:705–708. 2003.PubMed/NCBI

32 

Ito E, Yana I, Fujita C, Irifune A, Takeda M, Madachi A, Mori S, Hamada Y, Kawaguchi N and Matsuura N: The role of MT2-MMP in cancer progression. Biochem Biophys Res Commun. 393:222–227. 2010. View Article : Google Scholar : PubMed/NCBI

33 

Chen L, Zhou Q, Xu B, Liu J, Shi L, Zhu D, Wu C and Jiang J: MT2-MMP expression associates with tumor progression and angiogenesis in human lung cancer. Int J Clin Exp Pathol. 7:3469–3477. 2014.PubMed/NCBI

34 

Ii M, Yamamoto H, Taniguchi H, Adachi Y, Nakazawa M, Ohashi H, Tanuma T, Sukawa Y, Suzuki H, Sasaki S, et al: Co-expression of laminin β3 and γ2 chains and epigenetic inactivation of laminin α3 chain in gastric cancer. Int J Oncol. 39:593–599. 2011.PubMed/NCBI

35 

Miller KA, Chung J, Lo D, Jones JC, Thimmapaya B and Weitzman SA: Inhibition of laminin-5 production in breast epithelial cells by overexpression of p300. J Biol Chem. 275:8176–8182. 2000. View Article : Google Scholar : PubMed/NCBI

36 

Shevde LA and Samant RS: Role of osteopontin in the pathophysiology of cancer. Matrix Biol. 37:131–141. 2014. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
APA
Inagaki, Y., Shiraki, K., Sugimoto, K., Yada, T., Tameda, M., Ogura, S. ... Ito, M. (2016). Epigenetic regulation of proliferation and invasion in hepatocellular carcinoma cells by CBP/p300 histone acetyltransferase activity. International Journal of Oncology, 48, 533-540. https://doi.org/10.3892/ijo.2015.3288
MLA
Inagaki, Y., Shiraki, K., Sugimoto, K., Yada, T., Tameda, M., Ogura, S., Yamamoto, N., Takei, Y., Ito, M."Epigenetic regulation of proliferation and invasion in hepatocellular carcinoma cells by CBP/p300 histone acetyltransferase activity". International Journal of Oncology 48.2 (2016): 533-540.
Chicago
Inagaki, Y., Shiraki, K., Sugimoto, K., Yada, T., Tameda, M., Ogura, S., Yamamoto, N., Takei, Y., Ito, M."Epigenetic regulation of proliferation and invasion in hepatocellular carcinoma cells by CBP/p300 histone acetyltransferase activity". International Journal of Oncology 48, no. 2 (2016): 533-540. https://doi.org/10.3892/ijo.2015.3288