Histone Deacetylase Inhibitor Trichostatin A Suppresses Cell Proliferation and Induces Apoptosis by Regulating the PI3K/AKT Signalling Pathway in Gastric Cancer Cells

Author(s): Xinli An, Zekun Wei, Botian Ran, Hao Tian, Hongyu Gu, Yan Liu, Hongjuan Cui*, Shunqin Zhu*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 17 , 2020


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Graphical Abstract:


Abstract:

Background: Gastric cancer, a common malignant tumour worldwide, has a relatively poor prognosis and is a serious threat to human health. Histone Deacetylase Inhibitors (HDACi) are anticancer agents that are known to affect the cell growth of different cancer types. Trichostatin A (TSA) selectively inhibits the class I and II mammalian Histone Deacetylase (HDAC) family enzymes and regulates many cell processes. Still, the underlying mechanisms of HDACs are not fully understood in gastric cancer.

Objective: This study aims to investigate the antitumor effect and the mechanism of growth modulation of gastric cancer cells by TSA.

Methods: The cell proliferation of gastric cancer cells was measured by MTT and BrdU immunofluorescence assays. Soft agar assay was used to detect the colony formation ability of gastric cancer cells. Flow cytometry was used to examine cell cycle and apoptosis. Western blot was employed to detect protein expression of target factors.

Results: TSA inhibits the proliferation of MKN-45 and SGC-7901 cells and leads to significant repression of colony number and size. Flow cytometry assays show TSA induces cell cycle arrest at G1 phase and apoptosis, and TSA effects the expression of related factors in the mitochondrial apoptotic signalling and cell cycle-related regulatory pathways. Furthermore, TSA increased histone H3K27 acetylation and downregulated the expression of PI3K and p-AKT.

Conclusion: Downregulating PI3K/AKT pathway activation is involved in TSA-mediated proliferation inhibition of gastric cancer.

Keywords: Trichostatin A (TSA), proliferation, apoptosis, PI3K/AKT, gastric cancer, inhibitor.

[1]
Lee, H.J.; Song, I.C.; Yun, H.J.; Jo, D.Y.; Kim, S. CXC chemokines and chemokine receptors in gastric cancer: From basic findings towards therapeutic targeting. World J. Gastroenterol., 2014, 20(7), 1681-1693.
[http://dx.doi.org/10.3748/wjg.v20.i7.1681] [PMID: 24587647]
[2]
Li, B.; Liu, H.Y.; Guo, S.H.; Sun, P.; Gong, F.M.; Jia, B.Q. Detection of microsatellite instability in gastric cancer and dysplasia tissues. Int. J. Clin. Exp. Med., 2015, 8(11), 21442-21447.
[PMID: 26885089]
[3]
Lee, H.S.; Kim, W.H.; Kwak, Y.; Koh, J.; Bae, J.M.; Kim, K.M.; Chang, M.S.; Han, H.S.; Kim, J.M.; Kim, H.W.; Chang, H.K.; Choi, Y.H.; Park, J.Y.; Gu, M.J.; Lhee, M.J.; Kim, J.Y.; Kim, H.S.; Cho, M.Y. Gastrointestinal Pathology Study Group of Korean Society of Pathologists; Molecular Pathology Study Group of Korean Society of Pathologists. Molecular testing for gastrointestinal cancer. J. Pathol. Transl. Med., 2017, 51(2), 103-121.
[http://dx.doi.org/10.4132/jptm.2017.01.24] [PMID: 28219002]
[4]
Frei, E., III Clinical cancer research: An embattled species. Cancer, 1982, 50(10), 1979-1992.
[http://dx.doi.org/10.1002/1097-0142(19821115)50:10<1979:AID-CNCR2820501002>3.0.CO;2-D] [PMID: 7127245]
[5]
Wu, H.; Wang, W.; Tong, S.; Wu, C. Nucleostemin regulates proliferation and migration of gastric cancer and correlates with its malignancy. Int. J. Clin. Exp. Med., 2015, 8(10), 17634-17643.
[PMID: 26770353]
[6]
Song, Z.; Wu, Y.; Yang, J.; Yang, D.; Fang, X. Progress in the treatment of advanced gastric cancer. Tumour Biol., 2017, 39(7)1010428317714626
[http://dx.doi.org/10.1177/1010428317714626] [PMID: 28671042]
[7]
Cui, J.; Wang, W.; Li, Z.; Zhang, Z.; Wu, B.; Zeng, L. Epigenetic changes in osteosarcoma. Bull. Cancer, 2011, 98(7), E62-E68.
[http://dx.doi.org/10.1684/bdc.2011.1400] [PMID: 21708514]
[8]
Delgado-Calle, J.; Sañudo, C.; Sánchez-Verde, L.; García-Renedo, R.J.; Arozamena, J.; Riancho, J.A. Epigenetic regulation of alkaline phosphatase in human cells of the osteoblastic lineage. Bone, 2011, 49(4), 830-838.
[http://dx.doi.org/10.1016/j.bone.2011.06.006] [PMID: 21700004]
[9]
Wolffe, A.P.; Guschin, D. Review: Chromatin structural features and targets that regulate transcription. J. Struct. Biol., 2000, 129(2-3), 102-122.
[http://dx.doi.org/10.1006/jsbi.2000.4217] [PMID: 10806063]
[10]
Minucci, S.; Pelicci, P.G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer, 2006, 6(1), 38-51.
[http://dx.doi.org/10.1038/nrc1779] [PMID: 16397526]
[11]
Reichert, N.; Choukrallah, M.A.; Matthias, P. Multiple roles of class I HDACs in proliferation, differentiation, and development. Cell. Mol. Life Sci., 2012, 69(13), 2173-2187.
[http://dx.doi.org/10.1007/s00018-012-0921-9] [PMID: 22286122]
[12]
Gaymes, T.J.; Padua, R.A.; Pla, M.; Orr, S.; Omidvar, N.; Chomienne, C.; Mufti, G.J.; Rassool, F.V. Histone Deacetylase Inhibitors (HDI) cause DNA damage in leukemia cells: A mechanism for leukemia-specific HDI-dependent apoptosis? Mol. Cancer Res., 2006, 4(8), 563-573.
[http://dx.doi.org/10.1158/1541-7786.MCR-06-0111] [PMID: 16877702]
[13]
Gray, S.G.; Ekström, T.J. The human histone deacetylase family. Exp. Cell Res., 2001, 262(2), 75-83.
[http://dx.doi.org/10.1006/excr.2000.5080] [PMID: 11139331]
[14]
Chittur, S.V.; Sangster-Guity, N.; McCormick, P.J. Histone deacetylase inhibitors: A new mode for inhibition of cholesterol metabolism. BMC Genomics, 2008, 9(1), 507-520.
[http://dx.doi.org/10.1186/1471-2164-9-507] [PMID: 18959802]
[15]
Nervi, C.; Borello, U.; Fazi, F.; Buffa, V.; Pelicci, P.G.; Cossu, G. Inhibition of histone deacetylase activity by trichostatin A modulates gene expression during mouse embryogenesis without apparent toxicity. Cancer Res., 2001, 61(4), 1247-1249.
[PMID: 11245412]
[16]
Chen, X.; Xiao, W.; Chen, W.; Luo, L.; Ye, S.; Liu, Y. The epigenetic modifier trichostatin A, a histone deacetylase inhibitor, suppresses proliferation and epithelial-mesenchymal transition of lens epithelial cells. Cell Death Dis., 2013, 4(10)e884
[http://dx.doi.org/10.1038/cddis.2013.416] [PMID: 24157878]
[17]
Ropero, S.; Esteller, M. The role of Histone Deacetylases (HDACs) in human cancer. Mol. Oncol., 2007, 1(1), 19-25.
[http://dx.doi.org/10.1016/j.molonc.2007.01.001] [PMID: 19383284]
[18]
New, M.; Olzscha, H.; La Thangue, N.B. HDAC inhibitor-based therapies: can we interpret the code? Mol. Oncol., 2012, 6(6), 637-656.
[http://dx.doi.org/10.1016/j.molonc.2012.09.003] [PMID: 23141799]
[19]
Bonfils, C.; Walkinshaw, D.R.; Besterman, J.M.; Yang, X.J.; Li, Z. Pharmacological inhibition of histone deacetylases for the treatment of cancer, neurodegenerative disorders and inflammatory diseases. Expert Opin. Drug Discov., 2008, 3(9), 1041-1065.
[http://dx.doi.org/10.1517/17460441.3.9.1041] [PMID: 23506179]
[20]
Marks, P.; Rifkind, R.A.; Richon, V.M.; Breslow, R.; Miller, T.; Kelly, W.K. Histone deacetylases and cancer: Causes and therapies. Nat. Rev. Cancer, 2001, 1(3), 194-202.
[http://dx.doi.org/10.1038/35106079] [PMID: 11902574]
[21]
Zhang, J.; Roberts, T.M.; Shivdasani, R.A. Targeting PI3K signaling as a therapeutic approach for colorectal cancer. Gastroenterology, 2011, 141(1), 50-61.
[http://dx.doi.org/10.1053/j.gastro.2011.05.010] [PMID: 21723986]
[22]
Chen, C.S.; Weng, S.C.; Tseng, P.H.; Lin, H.P.; Chen, C.S. Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J. Biol. Chem., 2005, 280(46), 38879-38887.
[http://dx.doi.org/10.1074/jbc.M505733200] [PMID: 16186112]
[23]
Spiegel, S.; Milstien, S.; Grant, S. Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy. Oncogene, 2012, 31(5), 537-551.
[http://dx.doi.org/10.1038/onc.2011.267] [PMID: 21725353]
[24]
Tang, J.; Yan, H.; Zhuang, S. Histone deacetylases as targets for treatment of multiple diseases. Clin. Sci. (Lond.), 2013, 124(11), 651-662.
[http://dx.doi.org/10.1042/CS20120504] [PMID: 23414309]
[25]
Xiong, K.; Zhang, H.; Du, Y.; Tian, J.; Ding, S. Identification of HDAC9 as a viable therapeutic target for the treatment of gastric cancer. Exp. Mol. Med., 2019, 51(8), 1-15.
[http://dx.doi.org/10.1038/s12276-019-0301-8] [PMID: 31451695]
[26]
Hoshino, I.; Matsubara, H. Recent advances in histone deacetylase targeted cancer therapy. Surg. Today, 2010, 40(9), 809-815.
[http://dx.doi.org/10.1007/s00595-010-4300-6] [PMID: 20740342]
[27]
Watson, J.A.; McKenna, D.J.; Maxwell, P.; Diamond, J.; Arthur, K.; McKelvey-Martin, V.J.; Hamilton, P.W. Hyperacetylation in prostate cancer induces cell cycle aberrations, chromatin reorganization and altered gene expression profiles. J. Cell. Mol. Med., 2010, 14(6B), 1668-1682.
[http://dx.doi.org/10.1111/j.1582-4934.2009.00835.x] [PMID: 19583812]
[28]
Rezaei, P.F.; Fouladdel, S.; Hassani, S.; Yousefbeyk, F.; Ghaffari, S.M.; Amin, G.; Azizi, E. Induction of apoptosis and cell cycle arrest by pericarp polyphenol-rich extract of Baneh in human colon carcinoma HT29 cells. Food Chem. Toxicol., 2012, 50(3-4), 1054-1059.
[http://dx.doi.org/10.1016/j.fct.2011.11.012] [PMID: 22119783]
[29]
Li, G.C.; Zhang, X.; Pan, T.J.; Chen, Z.; Ye, Z.Q. Histone deacetylase inhibitor trichostatin A inhibits the growth of bladder cancer cells through induction of p21WAF1 and G1 cell cycle arrest. Int. J. Urol., 2006, 13(5), 581-586.
[http://dx.doi.org/10.1111/j.1442-2042.2006.01344.x] [PMID: 16771729]
[30]
Gérard, C.; Goldbeter, A. From quiescence to proliferation: Cdk oscillations drive the mammalian cell cycle. Front. Physiol., 2012, 3, 413.
[http://dx.doi.org/10.3389/fphys.2012.00413] [PMID: 23130001]
[31]
Gulappa, T.; Reddy, R.S.; Suman, S.; Nyakeriga, A.M.; Damodaran, C. Molecular interplay between cdk4 and p21 dictates G0/G1 cell cycle arrest in prostate cancer cells. Cancer Lett., 2013, 337(2), 177-183.
[http://dx.doi.org/10.1016/j.canlet.2013.05.014] [PMID: 23684928]
[32]
Aguero, M.F.; Facchinetti, M.M.; Sheleg, Z.; Senderowicz, A.M. Phenoxodiol, a novel isoflavone, induces G1 arrest by specific loss in cyclin-dependent kinase 2 activity by p53-lndependent induction of p21WAF1/CIP1. Cancer Res., 2005, 65(8), 3364-3373.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-2429] [PMID: 15833870]
[33]
Jang, H.H. Regulation of protein degradation by proteasomes in cancer. J. Cancer Prev., 2018, 23(4), 153-161.
[http://dx.doi.org/10.15430/JCP.2018.23.4.153] [PMID: 30671397]
[34]
Piatkov, K.I.; Brower, C.S.; Varshavsky, A. The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments. Proc. Natl. Acad. Sci. USA, 2012, 109(27), E1839-E1847.
[http://dx.doi.org/10.1073/pnas.1207786109] [PMID: 22670058]
[35]
Varshavsky, A. The N-end rule and regulation of apoptosis. Nat. Cell Biol., 2003, 5(5), 373-376.
[http://dx.doi.org/10.1038/ncb0503-373] [PMID: 12724766]
[36]
Eldeeb, M.A.; Ragheb, M.A.; Fon, E.A. Cell death: N-degrons fine-tune pyroptotic cell demise. Curr. Biol., 2019, 29(12), R588-R591.
[http://dx.doi.org/10.1016/j.cub.2019.05.004] [PMID: 31211982]
[37]
Eldeeb, M.A.; Fahlman, R.P. Phosphorylation impacts N-end rule degradation of the proteolytically activated form of BMX kinase. J. Biol. Chem., 2016, 291(43), 22757-22768.
[http://dx.doi.org/10.1074/jbc.M116.737387] [PMID: 27601470]
[38]
Cao, X.; Deng, X.; May, W.S. Cleavage of Bax to p18 Bax accelerates stress-induced apoptosis, and a cathepsin-like protease may rapidly degrade p18 Bax. Blood, 2003, 102(7), 2605-2614.
[http://dx.doi.org/10.1182/blood-2003-01-0211] [PMID: 12816867]
[39]
Chen, D.; Zhou, Q. Caspase cleavage of Bim_(EL) triggers a positive feedback amplification of apoptotic signaling. Proc. Natl. Acad. Sci. USA, 2004, 101(5), 1235-1240.
[40]
Dizin, E.; Ray, H.; Suau, F.; Voeltzel, T.; Dalla Venezia, N. Caspase-dependent BRCA1 cleavage facilitates chemotherapy-induced apoptosis. Apoptosis, 2008, 13(2), 237-246.
[http://dx.doi.org/10.1007/s10495-007-0167-4] [PMID: 18071904]
[41]
Yang, J.Y.; Michod, D.; Walicki, J.; Murphy, B.M.; Kasibhatla, S.; Martin, S.J.; Widmann, C. Partial cleavage of RasGAP by caspases is required for cell survival in mild stress conditions. Mol. Cell. Biol., 2004, 24(23), 10425-10436.
[http://dx.doi.org/10.1128/MCB.24.23.10425-10436.2004] [PMID: 15542850]
[42]
Green, D.R.; Llambi, F. Cell Death Signaling. Cold Spring Harb. Perspect. Biol., 2015, 7(12)a006080
[http://dx.doi.org/10.1101/cshperspect.a006080] [PMID: 26626938]
[43]
McIlwain, D.R.; Berger, T.; Mak, T.W. Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol., 2013, 5(4)a008656
[http://dx.doi.org/10.1101/cshperspect.a008656] [PMID: 23545416]
[44]
Shiozaki, E.N.; Chai, J.; Shi, Y. Oligomerization and activation of caspase-9, induced by Apaf-1 CARD. Proc. Natl. Acad. Sci. USA, 2002, 99(7), 4197-4202.
[http://dx.doi.org/10.1073/pnas.072544399] [PMID: 11904389]
[45]
Acehan, D.; Jiang, X.; Morgan, D.G.; Heuser, J.E.; Wang, X.; Akey, C.W. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol. Cell, 2002, 9(2), 423-432.
[http://dx.doi.org/10.1016/S1097-2765(02)00442-2] [PMID: 11864614]
[46]
Eldeeb, M.; Fahlman, R.; Esmaili, M.; Ragheb, M. Regulating apoptosis by degradation: The N-end rule-mediated regulation of apoptotic proteolytic fragments in mammalian cells. Int. J. Mol. Sci., 2018, 19(11), 3414-3441.
[http://dx.doi.org/10.3390/ijms19113414]
[47]
Wang, L.; Qian, L. miR-24 regulates intrinsic apoptosis pathway in mouse cardiomyocytes. PLoS One, 2014, 9(1)e85389
[http://dx.doi.org/10.1371/journal.pone.0085389] [PMID: 24454859]
[48]
Dabir, S.; Kluge, A.; McColl, K.; Liu, Y.; Lam, M.; Halmos, B.; Wildey, G.; Dowlati, A. PIAS3 activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status. Int. J. Cancer, 2014, 134(5), 1045-1054.
[http://dx.doi.org/10.1002/ijc.28448] [PMID: 23959540]
[49]
Zhu, S.; Evans, S.; Yan, B.; Povsic, T.J.; Tapson, V.; Goldschmidt-Clermont, P.J.; Dong, C. Transcriptional regulation of Bim by FOXO3a and Akt mediates scleroderma serum-induced apoptosis in endothelial progenitor cells. Circulation, 2008, 118(21), 2156-2165.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.787200] [PMID: 18981303]
[50]
Luo, J.; Manning, B.D.; Cantley, L.C. Targeting the PI3K-Akt pathway in human cancer: Rationale and promise. Cancer Cell, 2003, 4(4), 257-262.
[http://dx.doi.org/10.1016/S1535-6108(03)00248-4] [PMID: 14585353]
[51]
Woodgett, J.R. Recent advances in the protein kinase B signaling pathway. Curr. Opin. Cell Biol., 2005, 17(2), 150-157.
[http://dx.doi.org/10.1016/j.ceb.2005.02.010] [PMID: 15780591]


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VOLUME: 20
ISSUE: 17
Year: 2020
Published on: 27 June, 2020
Page: [2114 - 2124]
Pages: 11
DOI: 10.2174/1871520620666200627204857
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