title: Susceptibility of hepatoma-derived cells to histone deacetylase inhibitors is associated with ID2 expression.
abstract: Downregulation of inhibitor of DNA binding 2 (ID2) is associated with poor prognosis in cases of hepatocellular carcinoma (HCC). Therefore, to search for effective antitumor drugs for the treatment of HCC exhibiting poor prognostic indicators, we used two HCC-derived cell lines (HuH-7 and HLE) to alter ID2 levels. Specifically, ID2 expression was knocked down in HuH-7 cells via transfection with ID2-specific small interfering RNAs and separately ID2 was overexpressed in HLE cells via an ID2 expression plasmid vector. To assess the effect of antitumor drugs, MTS assay was performed. Annexin V staining was used to evaluate apoptosis and real-time RT-PCR was used to measure mRNA levels. ID2 knockdown cells were more susceptible to histone deacethylase (HDAC) inhibitors including sodium butyrate (NaB), sodium 4-phenyl-butyrate, tricostatin A, suberoylanilide hydroxamic acid, MS-275, apicidin and HC-toxin. Conversely, cells that overexpressed ID2 were less susceptible than control cells to HDAC inhibitors. NaB-induced apoptosis was inversely correlated with ID2 expression. Expression of the anti-apoptotic mRNA BCL2 was induced by NaB in control cells, but this induction of BCL2 was inhibited by ID2 knockdown and strengthened by ID2 overexpression. Expression of another anti-apoptotic mRNA, BCL2L1, was decreased by NaB administration and then partially recovered. However, in ID2 knockdown cells, BCL2L1 levels did not recover from NaB-induced suppression. ID2 affected the susceptibility of two HCC-derived cell lines to an HDAC inhibitor by regulating the expression of anti-apoptotic genes. Therefore, HDAC inhibitors may be effective for the treatment of HCC for which the prognosis is poor based on ID2 downregulation and ID2 could serve as a marker that is predictive of the clinical response to HDAC inhibitors.
authors: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
authors: Ryouichi
authors: R
authors: Tsunedomi
authors: Norio
authors: N
authors: Iizuka
authors: Sawako
authors: S
authors: Harada
authors: Masaaki
authors: M
authors: Oka
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2
references: J Hepatol. 2004 Feb;40(2):278-84
references: 14739099
references: Cell Mol Life Sci. 2001 May;58(5-6):728-36
references: 11437234
references: Clin Cancer Res. 2004 Nov 15;10(22):7475-83
references: 15569977
references: Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1512-6
references: 1741406
references: Mol Cancer Ther. 2003 Dec;2(12):1273-84
references: 14707268
references: Cancer Res. 2000 Mar 1;60(5):1332-40
references: 10728695
references: Int J Oncol. 2005 Feb;26(2):319-27
references: 15645115
references: Nat Genet. 2002 Aug;31(4):339-46
references: 12149612
references: Am J Pathol. 1999 Sep;155(3):815-22
references: 10487839
references: Clin Cancer Res. 2008 Feb 15;14(4):1025-31
references: 18281534
references: Cancer Res. 2001 Dec 15;61(24):8803-10
references: 11751402
references: Adv Cancer Res. 2004;92:81-94
references: 15530557
references: J Biol Chem. 2001 Nov 9;276(45):42084-90
references: 11551946
references: Clin Cancer Res. 2003 Feb;9(2):779-85
references: 12576450
references: Cancer Res. 2003 Nov 1;63(21):7098-105
references: 14612502
references: J Hepatol. 2004 Sep;41(3):436-45
references: 15336447
references: Cancer Res. 2000 Nov 1;60(21):5929-33
references: 11085505
references: J Natl Cancer Inst. 2000 Aug 2;92(15):1210-6
references: 10922406
references: Cancer Cell. 2004 Mar;5(3):215-9
references: 15050913
references: Immunol Cell Biol. 2012 Jan;90(1):85-94
references: 22124371
references: Oncogene. 2004 Aug 19;23(37):6304-15
references: 15318170
references: Int J Oncol. 2008 Oct;33(4):637-46
references: 18813776
references: Oncogene. 2001 Dec 20;20(58):8308-16
references: 11840323
references: Int J Cancer. 2005 Jun 20;115(3):403-11
references: 15688367
references: Oncogene. 2001 Dec 20;20(58):8334-41
references: 11840326
references: Clin Cancer Res. 2006 Dec 1;12(23):6910-9
references: 17145808
references: Med Res Rev. 2006 Jul;26(4):397-413
references: 16450343
references: J Biol Chem. 1994 Jan 21;269(3):2139-45
references: 8294468
references: Int J Oncol. 2006 Dec;29(6):1445-51
references: 17088983
references: Cancer Treat Rev. 2006 May;32(3):157-65
references: 16516391
references: Oncogene. 2001 Dec 20;20(58):8317-25
references: 11840324
references: Cancer Res. 1999 Apr 1;59(7 Suppl):1726s-1730s
references: 10197587
references: Annu Rev Pharmacol Toxicol. 2005;45:495-528
references: 15822187
references: Anticancer Drugs. 2002 Jan;13(1):1-13
references: 11914636
references: Clin Cancer Res. 2004 Mar 15;10(6):2044-51
references: 15041724
references: Oncogene. 2005 Jul 7;24(29):4721-7
references: 15897910
references: Cell Growth Differ. 1993 Jan;4(1):49-55
references: 8424906
references: FEBS Lett. 2005 Feb 14;579(5):1089-100
references: 15710396
references: Genes Dev. 2011 Dec 15;25(24):2610-8
references: 22016339
references: Curr Opin Genet Dev. 1999 Feb;9(1):40-8
references: 10072350
references: Int J Oncol. 2010 Jan;36(1):205-12
references: 19956849
references: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references: 15761078
references: Cancer Res. 2000 Jan 15;60(2):262-5
references: 10667572
references: Mol Cell Biol. 1996 Sep;16(9):4673-82
references: 8756624
references: Oncogene. 2007 Aug 13;26(37):5541-52
references: 17694093
references: Cancer. 2005 Sep 1;104(5):1037-44
references: 15999366
references: Nature. 1999 Oct 14;401(6754):670-7
references: 10537105
references: Cell. 1990 Apr 6;61(1):49-59
references: 2156629
references: J Cell Sci. 2000 Nov;113 ( Pt 22):3897-905
references: 11058077
references: EMBO J. 1992 Jul;11(7):2563-71
references: 1628620