Ku70 is essential for histone deacetylase inhibitor trichostatin A-induced apoptosis

Meng,Jin; Zhang,Feng; Zhang,Xu‑Tao; Zhang,Tao; Li,Yu‑Hua; Fan,Lei; Sun,Yang; Zhang,He‑Long; Mei,Qi‑Bing

doi:10.3892/mmr.2015.3358

Ku70 is essential for histone deacetylase inhibitor trichostatin A-induced apoptosis

Authors:
- Jin Meng
- Feng Zhang
- Xu‑Tao Zhang
- Tao Zhang
- Yu‑Hua Li
- Lei Fan
- Yang Sun
- He‑Long Zhang
- Qi‑Bing Mei
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Affiliations: Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of The State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China, Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
Published online on: February 16, 2015 https://doi.org/10.3892/mmr.2015.3358
Pages: 581-586

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Abstract

It was previously reported that the histone deacetylase inhibitor (HDACI) trichostatin A (TSA) induced B cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax)‑dependent apoptosis in colorectal cancer (CRC) cells. In addition, Ku70 has been identified as a regulator of apoptosis, the mechanism of which proceeds via interacting with Bax. The aim of the present study was to investigate the role of Ku70 in TSA‑induced apoptosis in the CRC cell lines HCT116 and HT29. The results showed that TSA induced the acetylation of Ku70, which was found to be associated with increased apoptosis. In addition, TSA treatment promoted the release of Bax from its complex with Ku70. Bax was then detected to have translocated from the cytoplasm into the mitochondria, while cytochrome c was detected to have translocated from the mitochondria into the cytoplasm. Furthermore, knockdown of Ku70 using small interfering RNA decreased TSA‑induced apoptosis as well as downregulated the expression of Bax. These effects were rescued through pre‑treatment of cells with the proteasome inhibitor MG132. In conclusion, the results of the present study suggested that Ku70 acetylation mediated TSA‑induced apoptosis in CRC cells. In addition, Ku70 was found to be indispensable in TSA‑induced apoptosis due to its role in protecting Bax from proteosomal degradation.

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1	Jernal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar
2	Johnstone RW: Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 1:287–299. 2002. View Article : Google Scholar : PubMed/NCBI
3	Yu X, Guo ZS, Marcu MG, et al: Modulation of p53, ErbB1, ErbB2 and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst. 94:504–513. 2002. View Article : Google Scholar : PubMed/NCBI
4	Zhu WG and Otterson GA: The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anti-Cancer Agents. 3:187–199. 2003. View Article : Google Scholar
5	Meinke PT and Liberator P: Histone deacetylase: a target for antipro-liferative and antiprotozoal agents. Curr Med Chem. 8:211–235. 2001. View Article : Google Scholar : PubMed/NCBI
6	Yoshida M, Kijima M, Akita M and Beppu T: Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem. 265:17174–17179. 1990.PubMed/NCBI
7	Meng J, Zhang HH, Zhou CX, Li C, Zhang F and Mei QB: The histone deacetylase inhibitor trichostatin A induces cell cycle arrest and apoptosis in colorectal cancer cells via p53-dependent and -independent pathways. Oncol Rep. 28:384–388. 2012.PubMed/NCBI
8	Sawada M, Sun W, Hayes P, Leskov K, Boothman DA and Matsuyama S: Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol. 5:320–329. 2003. View Article : Google Scholar : PubMed/NCBI
9	Cohen HY, Lavu S, Bitterman KJ, et al: Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell. 13:627–638. 2004. View Article : Google Scholar : PubMed/NCBI
10	Zhang F, Bäumer N, Rode M, et al: The inhibitor of growth protein 5 (ING5) depends on INCA1 as a co-factor for its antiproliferative effects. PLoS One. 6:e215052011. View Article : Google Scholar : PubMed/NCBI
11	Kroemer G: Mitochondrial implication in apoptosis: towards an endosymbiont hypothesis of apoptosis evolution. Cell Death Differ. 4:443–456. 1997. View Article : Google Scholar : PubMed/NCBI
12	Reed JC: Cytochrome c: can’t live with it-can’t live without it. Cell. 91:559–562. 1997. View Article : Google Scholar : PubMed/NCBI
13	Lindemann RK, Gabrielli B and Johnstone RW: Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle. 3:779–788. 2004. View Article : Google Scholar : PubMed/NCBI
14	De Giorgi F, Lartigue L, Bauer MK, et al: The permeability transition pore signals apoptosis by directing Bax translocation and multimerization. FASEB J. 16:607–609. 2002.PubMed/NCBI
15	Subramanian C, Hada M, Opipari AW Jr, Castle VP and Kwok RP: CREB-binding protein regulates Ku70 acetylation in response to ionization radiation in neuroblastoma. Mol Cancer Res. 11:173–181. 2013. View Article : Google Scholar :
16	Collis SJ, DeWeese TL, Jeggo PA, et al: The life and death of DNA-PK. Oncogene. 24:949–961. 2005. View Article : Google Scholar
17	He F, Li L, Kim D, et al: Adenovirus-mediated expression of a dominant negative Ku70 fragment radiosensitizes human tumor cells under aerobic and hypoxic conditions. Cancer Res. 67:634–642. 2007. View Article : Google Scholar : PubMed/NCBI
18	Shintani S, Mihara M, Li C, et al: Up-regulation of DNA- dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma. Cancer Sci. 94:894–900. 2003. View Article : Google Scholar : PubMed/NCBI
19	Hashimoto M, Rao S, Tokuno O, et al: DNA-PK: the major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway. J Radiat Res. 44:151–159. 2003. View Article : Google Scholar : PubMed/NCBI
20	Com E, Lagadec C, Page A, et al: Nerve growth factor receptor TrkA signaling in breast cancer cells involves Ku70 to prevent apoptosis. Mol Cell Proteomics. 6:1842–1854. 2007. View Article : Google Scholar : PubMed/NCBI
21	Lee JC, Lee CH, Su CL, et al: Justicidin A decreases the level of cytosolic Ku70 leading toapoptosis in human colorectal cancer cells. Carcinogenesis. 26:1716–1730. 2005. View Article : Google Scholar : PubMed/NCBI
22	Koike M, Yutoku Y and Koike A: The defect of Ku70 affects sensitivity to x-ray and radiation-induced caspase-dependent apoptosis in lung cells. J Vet Med Sci. 75:415–420. 2013. View Article : Google Scholar
23	Amsel AD, Rathaus M, Kronman N and Cohen HY: Regulation of the proapoptotic factor Bax by Ku70-dependent deubiquitylation. Cell Biol. 105:5117–5122. 2008.