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HDAC10 as a potential therapeutic target in ovarian cancer

Published:January 07, 2017DOI:https://doi.org/10.1016/j.ygyno.2017.01.009

      Highlights

      • HDAC10 is deleted in 5–10% of ovarian cancers.
      • Decrease in HDAC10 expression is associated with sensitivity to platinum therapy.
      • HDAC inhibitors increase the sensitivity of ovarian cancer cells to cisplatin.
      • Depletion of HDAC10 increases the sensitivity of ovarian cancer cells to cisplatin.
      • We suggest HDAC10-specific inhibitors could prolong sensitivity to platinum therapy.

      Abstract

      Objective

      We analyzed histone deacetylase 10 (HDAC10) for function in the context of the DNA damage response in BRCA1-null ovarian cancer cells as well as evaluated the potential of general HDAC inhibitors in primary ovarian carcinoma cells. HDAC10 had previously been shown to be highly stimulatory to the process of homology directed repair in HeLa cells, and in this study we investigated whether HDAC10 could impact in vitro the response to anticancer therapies. We hypothesized that the loss of HDAC10 would sensitize cells to platinum therapy.

      Methods

      We combined informatics analysis of large DNA sequencing datasets from ovarian cancer tumors with tissue culture based assays of primary and established cell lines to test for sensitivity to platinum therapy if HDAC10 activity was inhibited or depleted.

      Results

      Using The Cancer Genome Atlas (TCGA) dataset, we found that deep deletions in HDAC10 occurred in 5–10% of ovarian cancer tumors. From the TCGA data we found that low HDAC10 mRNA levels correlated with platinum sensitivity of the tumors. Cell proliferation and DNA damage assays in a BRCA1-null ovarian carcinoma cell line demonstrated reduced DNA repair capacity and sensitization of platinum therapy. Similarly, primary ovarian carcinoma cells demonstrated a sensitization to platinum therapies when treated with HDAC inhibitors.

      Conclusions

      From the results of this study, we suggest that the inhibition of HDAC10 may potentiate the effects of platinum therapies in ovarian tumors.

      Keywords

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      References

        • Allfrey V.G.
        • Faulkner R.
        • Mirsky A.E.
        Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis.
        Proc. Natl. Acad. Sci. U. S. A. 1964; 51 (doi. PMC300163. http://www.ncbi.nlm.nih.gov/pubmed/14172992): 786-794
        • Brownell J.E.
        • Zhou J.
        • Ranalli T.
        • Kobayashi R.
        • Edmondson D.G.
        • Roth S.Y.
        • Allis C.D.
        Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation.
        Cell. 1996; 84 (http://www.ncbi.nlm.nih.gov/pubmed/8601308): 843-851
        • Bannister A.J.
        • Kouzarides T.
        Regulation of chromatin by histone modifications.
        Cell Res. 2011; 21 (PMC3193420. http://www.ncbi.nlm.nih.gov/pubmed/21321607): 381-395https://doi.org/10.1038/cr.2011.22
        • Torok M.S.
        • Grant P.A.
        Histone acetyltransferase proteins contribute to transcriptional processes at multiple levels.
        Adv. Protein Chem. 2004; 67 (http://www.ncbi.nlm.nih.gov/pubmed/14969728): 181-199https://doi.org/10.1016/S0065-3233(04)67007-0
        • Taunton J.
        • Hassig C.A.
        • Schreiber S.L.
        A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p.
        Science. 1996; 272 (http://www.ncbi.nlm.nih.gov/pubmed/8602529): 408-411
        • Choudhary C.
        • Kumar C.
        • Gnad F.
        • Nielsen M.L.
        • Rehman M.
        • Walther T.C.
        • Olsen J.V.
        • Mann M.
        Lysine acetylation targets protein complexes and co-regulates major cellular functions.
        Science. 2009; 325 (http://www.ncbi.nlm.nih.gov/pubmed/19608861): 834-840https://doi.org/10.1126/science.1175371
        • Glozak M.A.
        • Sengupta N.
        • Zhang X.
        • Seto E.
        Acetylation and deacetylation of non-histone proteins.
        Gene. 2005; 363 (http://www.ncbi.nlm.nih.gov/pubmed/16289629): 15-23https://doi.org/10.1016/j.gene.2005.09.010
        • Nan X.
        • Ng H.H.
        • Johnson C.A.
        • Laherty C.D.
        • Turner B.M.
        • Eisenman R.N.
        • Bird A.
        Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.
        Nature. 1998; 393 (http://www.ncbi.nlm.nih.gov/pubmed/9620804): 386-389https://doi.org/10.1038/30764
        • Bhaskara S.
        • Knutson S.K.
        • Jiang G.
        • Chandrasekharan M.B.
        • Wilson A.J.
        • Zheng S.
        • Yenamandra A.
        • Locke K.
        • Yuan J.L.
        • Bonine-Summers A.R.
        • Wells C.E.
        • Kaiser J.F.
        • Washington M.K.
        • Zhao Z.
        • Wagner F.F.
        • Sun Z.W.
        • Xia F.
        • Holson E.B.
        • Khabele D.
        • Hiebert S.W.
        Hdac3 is essential for the maintenance of chromatin structure and genome stability.
        Cancer Cell. 2010; 18 (PMC3004468. http://www.ncbi.nlm.nih.gov/pubmed/21075309): 436-447https://doi.org/10.1016/j.ccr.2010.10.022
        • Heideman M.R.
        • Wilting R.H.
        • Yanover E.
        • Velds A.
        • de Jong J.
        • Kerkhoven R.M.
        • Jacobs H.
        • Wessels L.F.
        • Dannenberg J.H.
        Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function.
        Blood. 2013; 121 (PMC3596963. http://www.ncbi.nlm.nih.gov/pubmed/23327920): 2038-2050https://doi.org/10.1182/blood-2012-08-450916
        • Kotian S.
        • Liyanarachchi S.
        • Zelent A.
        • Parvin J.D.
        Histone deacetylases 9 and 10 are required for homologous recombination.
        J. Biol. Chem. 2011; 286 (PMC3048658. http://www.ncbi.nlm.nih.gov/pubmed/21247901): 7722-7726https://doi.org/10.1074/jbc.C110.194233
        • Metcalfe K.A.
        • Lynch H.T.
        • Ghadirian P.
        • Tung N.
        • Olivotto I.A.
        • Foulkes W.D.
        • Warner E.
        • Olopade O.
        • Eisen A.
        • Weber B.
        • McLennan J.
        • Sun P.
        • Narod S.A.
        The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers.
        Gynecol. Oncol. 2005; 96 (http://www.ncbi.nlm.nih.gov/pubmed/15589605): 222-226https://doi.org/10.1016/j.ygyno.2004.09.039
        • Miki Y.
        • Swensen J.
        • Shattuck-Eidens D.
        • Futreal P.A.
        • Harshman K.
        • Tavtigian S.
        • Liu Q.
        • Cochran C.
        • Bennett L.M.
        • Ding W.
        • et al.
        A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
        Science. 1994; 266 (http://www.ncbi.nlm.nih.gov/pubmed/7545954): 66-71
        • Farmer H.
        • McCabe N.
        • Lord C.J.
        • Tutt A.N.
        • Johnson D.A.
        • Richardson T.B.
        • Santarosa M.
        • Dillon K.J.
        • Hickson I.
        • Knights C.
        • Martin N.M.
        • Jackson S.P.
        • Smith G.C.
        • Ashworth A.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005; 434 (http://www.ncbi.nlm.nih.gov/pubmed/15829967): 917-921https://doi.org/10.1038/nature03445
        • Fleury H.
        • Carmona E.
        • Morin V.G.
        • Meunier L.
        • Masson J.Y.
        • Tonin P.N.
        • Provencher D.
        • Mes-Masson A.M.
        Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines.
        Oncotarget. 2016; (http://www.ncbi.nlm.nih.gov/pubmed/27374179)https://doi.org/10.18632/oncotarget.10308
        • Parvin J.
        • Chiba N.
        • Ransburgh D.
        Identifying the effects of BRCA1 mutations on homologous recombination using cells that express endogenous wild-type BRCA1.
        J. Vis. Exp. 2011; 48 (PMC3197403. http://www.ncbi.nlm.nih.gov/pubmed/21372787)https://doi.org/10.3791/2468
        • Shepherd T.G.
        • Theriault B.L.
        • Campbell E.J.
        • Nachtigal M.W.
        Primary culture of ovarian surface epithelial cells and ascites-derived ovarian cancer cells from patients.
        Nat. Protoc. 2006; 1 (http://www.ncbi.nlm.nih.gov/pubmed/17406520): 2643-2649https://doi.org/10.1038/nprot.2006.328
        • Saini U.
        • Naidu S.
        • ElNaggar A.C.
        • Bid H.K.
        • Wallbillich J.J.
        • Bixel K.
        • Bolyard C.
        • Suarez A.A.
        • Kaur B.
        • Kuppusamy P.
        • Hays J.
        • Goodfellow P.J.
        • Cohn D.E.
        • Selvendiran K.
        Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target.
        Oncogene. 2016; (http://www.ncbi.nlm.nih.gov/pubmed/27292260)https://doi.org/10.1038/onc.2016.197
        • Ransburgh D.J.
        • Chiba N.
        • Ishioka C.
        • Toland A.E.
        • Parvin J.D.
        Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination.
        Cancer Res. 2010; 70 (PMC2943742. http://www.ncbi.nlm.nih.gov/pubmed/20103620): 988-995https://doi.org/10.1158/0008-5472.CAN-09-2850
        • Towler W.I.
        • Zhang J.
        • Ransburgh D.J.
        • Toland A.E.
        • Ishioka C.
        • Chiba N.
        • Parvin J.D.
        Analysis of BRCA1 variants in double-strand break repair by homologous recombination and single-strand annealing.
        Hum. Mutat. 2013; 34 (PMC3906639. http://www.ncbi.nlm.nih.gov/pubmed/23161852): 439-445https://doi.org/10.1002/humu.22251
        • Tice R.R.
        • Agurell E.
        • Anderson D.
        • Burlinson B.
        • Hartmann A.
        • Kobayashi H.
        • Miyamae Y.
        • Rojas E.
        • Ryu J.C.
        • Sasaki Y.F.
        Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing.
        Environ. Mol. Mutagen. 2000; 35 (http://www.ncbi.nlm.nih.gov/pubmed/10737956): 206-221
        • MacDonald J.R.
        • Ziman R.
        • Yuen R.K.
        • Feuk L.
        • Scherer S.W.
        The Database of Genomic Variants: a curated collection of structural variation in the human genome.
        Nucleic Acids Res. 2014; 42 (PMC3965079. http://www.ncbi.nlm.nih.gov/pubmed/24174537): D986-D992https://doi.org/10.1093/nar/gkt958
        • Jakobsson M.
        • Scholz S.W.
        • Scheet P.
        • Gibbs J.R.
        • VanLiere J.M.
        • Fung H.C.
        • Szpiech Z.A.
        • Degnan J.H.
        • Wang K.
        • Guerreiro R.
        • Bras J.M.
        • Schymick J.C.
        • Hernandez D.G.
        • Traynor B.J.
        • Simon-Sanchez J.
        • Matarin M.
        • Britton A.
        • van de Leemput J.
        • Rafferty I.
        • Bucan M.
        • Cann H.M.
        • Hardy J.A.
        • Rosenberg N.A.
        • Singleton A.B.
        Genotype, haplotype and copy-number variation in worldwide human populations.
        Nature. 2008; 451 (http://www.ncbi.nlm.nih.gov/pubmed/18288195): 998-1003https://doi.org/10.1038/nature06742
        • Xu H.
        • Poh W.T.
        • Sim X.
        • Ong R.T.
        • Suo C.
        • Tay W.T.
        • Khor C.C.
        • Seielstad M.
        • Liu J.
        • Aung T.
        • Tai E.S.
        • Wong T.Y.
        • Chia K.S.
        • Teo Y.Y.
        SgD-CNV, a database for common and rare copy number variants in three Asian populations.
        Hum. Mutat. 2011; 32 (http://www.ncbi.nlm.nih.gov/pubmed/21882294): 1341-1349https://doi.org/10.1002/humu.21601
        • Cerami E.
        • Gao J.
        • Dogrusoz U.
        • Gross B.E.
        • Sumer S.O.
        • Aksoy B.A.
        • Jacobsen A.
        • Byrne C.J.
        • Heuer M.L.
        • Larsson E.
        • Antipin Y.
        • Reva B.
        • Goldberg A.P.
        • Sander C.
        • Schultz N.
        The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.
        Cancer Discov. 2012; 2 (PMC3956037. http://www.ncbi.nlm.nih.gov/pubmed/22588877): 401-404https://doi.org/10.1158/2159-8290.CD-12-0095
        • Gao J.
        • Aksoy B.A.
        • Dogrusoz U.
        • Dresdner G.
        • Gross B.
        • Sumer S.O.
        • Sun Y.
        • Jacobsen A.
        • Sinha R.
        • Larsson E.
        • Cerami E.
        • Sander C.
        • Schultz N.
        Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
        Sci. Signal. 2013; 6 (PMC4160307. p. pl1, http://www.ncbi.nlm.nih.gov/pubmed/23550210)https://doi.org/10.1126/scisignal.2004088
        • Jung Y.
        • Lippard S.J.
        Direct cellular responses to platinum-induced DNA damage.
        Chem. Rev. 2007; 107 (http://www.ncbi.nlm.nih.gov/pubmed/17455916): 1387-1407https://doi.org/10.1021/cr068207j
        • Dietrich III, C.S.
        • Greenberg V.L.
        • DeSimone C.P.
        • Modesitt S.C.
        • van Nagell J.R.
        • Craven R.
        • Zimmer S.G.
        Suberoylanilide hydroxamic acid (SAHA) potentiates paclitaxel-induced apoptosis in ovarian cancer cell lines.
        Gynecol. Oncol. 2010; 116 (http://www.ncbi.nlm.nih.gov/pubmed/19875160): 126-130https://doi.org/10.1016/j.ygyno.2009.09.039
        • West A.C.
        • Johnstone R.W.
        New and emerging HDAC inhibitors for cancer treatment.
        J. Clin. Invest. 2014; 124 (PMC3871231. http://www.ncbi.nlm.nih.gov/pubmed/24382387): 30-39https://doi.org/10.1172/JCI69738
        • Raaphorst G.P.
        • Leblanc M.
        • Li L.F.
        A comparison of response to cisplatin, radiation and combined treatment for cells deficient in recombination repair pathways.
        Anticancer Res. 2005; 25 (http://www.ncbi.nlm.nih.gov/pubmed/15816518): 53-58
        • Chen B.Y.
        • Huang C.H.
        • Lin Y.H.
        • Huang C.C.
        • Deng C.X.
        • Hsu L.C.
        The K898E germline variant in the PP1-binding motif of BRCA1 causes defects in DNA repair.
        Sci. Rep. 2014; 4 (PMC4108927. http://www.ncbi.nlm.nih.gov/pubmed/25056273): 5812https://doi.org/10.1038/srep05812
        • Agarwal R.
        • Kaye S.B.
        Ovarian cancer: strategies for overcoming resistance to chemotherapy.
        Nat. Rev. Cancer. 2003; 3 (http://www.ncbi.nlm.nih.gov/pubmed/12835670): 502-516https://doi.org/10.1038/nrc1123
        • Greenlee R.T.
        • Hill-Harmon M.B.
        • Murray T.
        • Thun M.
        Cancer statistics, 2001.
        CA Cancer J. Clin. 2001; 51 (http://www.ncbi.nlm.nih.gov/pubmed/11577478): 15-36
        • Modesitt S.C.
        • Sill M.
        • Hoffman J.S.
        • Bender D.P.
        • Gynecologic Oncology G.
        A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study.
        Gynecol. Oncol. 2008; 109 (http://www.ncbi.nlm.nih.gov/pubmed/18295319): 182-186https://doi.org/10.1016/j.ygyno.2008.01.009
        • Matulonis U.
        • Berlin S.
        • Lee H.
        • Whalen C.
        • Obermayer E.
        • Penson R.
        • Liu J.
        • Campos S.
        • Krasner C.
        • Horowitz N.
        Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer.
        Cancer Chemother. Pharmacol. 2015; 76 (http://www.ncbi.nlm.nih.gov/pubmed/26119093): 417-423https://doi.org/10.1007/s00280-015-2813-9
        • Mendivil A.A.
        • Micha J.P.
        • Brown 3rd, J.V.
        • Rettenmaier M.A.
        • Abaid L.N.
        • Lopez K.L.
        • Goldstein B.H.
        Increased incidence of severe gastrointestinal events with first-line paclitaxel, carboplatin, and vorinostat chemotherapy for advanced-stage epithelial ovarian, primary peritoneal, and fallopian tube cancer.
        Int. J. Gynecol. Cancer. 2013; 23 (http://www.ncbi.nlm.nih.gov/pubmed/23385285): 533-539https://doi.org/10.1097/IGC.0b013e31828566f1
        • Minucci S.
        • Pelicci P.G.
        Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer.
        Nat. Rev. Cancer. 2006; 6 (http://www.ncbi.nlm.nih.gov/pubmed/16397526): 38-51https://doi.org/10.1038/nrc1779
        • Ramalingam S.S.
        • Maitland M.L.
        • Frankel P.
        • Argiris A.E.
        • Koczywas M.
        • Gitlitz B.
        • Thomas S.
        • Espinoza-Delgado I.
        • Vokes E.E.
        • Gandara D.R.
        • Belani C.P.
        Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer.
        J. Clin. Oncol. 2010; 28 (PMC2799233. http://www.ncbi.nlm.nih.gov/pubmed/19933908): 56-62https://doi.org/10.1200/JCO.2009.24.9094
        • Ramalingam S.S.
        • Parise R.A.
        • Ramanathan R.K.
        • Lagattuta T.F.
        • Musguire L.A.
        • Stoller R.G.
        • Potter D.M.
        • Argiris A.E.
        • Zwiebel J.A.
        • Egorin M.J.
        • Belani C.P.
        Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies.
        Clin. Cancer Res. 2007; 13 (http://www.ncbi.nlm.nih.gov/pubmed/17510206): 3605-3610https://doi.org/10.1158/1078-0432.CCR-07-0162
        • Kim M.G.
        • Pak J.H.
        • Choi W.H.
        • Park J.Y.
        • Nam J.H.
        • Kim J.H.
        The relationship between cisplatin resistance and histone deacetylase isoform overexpression in epithelial ovarian cancer cell lines.
        J. Gynecol. Oncol. 2012; 23 (PMC3395014. http://www.ncbi.nlm.nih.gov/pubmed/22808361): 182-189https://doi.org/10.3802/jgo.2012.23.3.182