Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

Cancer Biology and Therapy

Volumn 15, Issue 6, 2014, Pages 742-757

  Rosik, Lorena ^a   Niegisch, Günter ^a   Fischer, Ute ^a   Jung, Manfred ^b,c   Schulz, Wolfgang Arthur ^a   Hoffmann, Michel̀e Janine ^a  

^a Department of Orthopedic Surgery   (Germany)

^b UNIVERSITY OF FREIBURG   (Germany)

^c GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

Author keywords

17 AAG; Bortezomib; HDAC; HDAC inhibitor; ST 80; Tubacin; Tubastatin; Urothelial cancer

Indexed keywords

17AAG; 4 [2 (5,6,7,8 TETRAHYDRO 5,5,8,8 TETRAMETHYL 2 NAPHTHYL)VINYL]BENZOIC ACID; BML GR 362; BORTEZOMIB; DOXORUBICIN; ETOPOSIDE; HISTONE DEACETYLASE 6; HISTONE DEACETYLASE INHIBITOR; S 1013; SMALL INTERFERING RNA; SML 0044; TANESPIMYCIN; TUBACIN; TUBASTATIN A; UNCLASSIFIED DRUG; VORINOSTAT; ANILIDE; ANTINEOPLASTIC AGENT; BENZOQUINONE DERIVATIVE; BORONIC ACID DERIVATIVE; HDAC6 PROTEIN, HUMAN; HISTONE; HISTONE DEACETYLASE; HYDROXAMIC ACID; INDOLE DERIVATIVE; MACROCYCLIC LACTAM; PYRAZINE DERIVATIVE;

ADULT; AGED; ARTICLE; CANCER CELL; CANCER GRADING; CANCER STAGING; CARCINOMA CELL LINE; CELL COUNT; CELL CYCLE ARREST; CELL DEATH; CELL PROLIFERATION; CELL STRESS; CELL SURVIVAL; CELL VIABILITY; CELL VIABILITY ASSAY; COMPARATIVE STUDY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DNA DAMAGE; DRUG EFFICACY; DRUG SENSITIVITY; DRUG TOXICITY; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME SPECIFICITY; FLOW CYTOMETRY; GENE SILENCING; GENETIC TRANSFECTION; HUMAN; HUMAN CELL; IC 50; IMMUNOFLUORESCENCE; LYMPH NODE METASTASIS; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; QUANTITATIVE ANALYSIS; REAL TIME POLYMERASE CHAIN REACTION; TRANSITIONAL CELL CARCINOMA; UPREGULATION; VERY ELDERLY; WESTERN BLOTTING; ACETYLATION; DRUG EFFECTS; DRUG SCREENING; ENZYMOLOGY; GENE EXPRESSION; GENETICS; IC50; METABOLISM; MIDDLE AGED; PATHOLOGY; PROTEIN PROCESSING; TUMOR CELL LINE; URINARY BLADDER NEOPLASMS; UROTHELIUM;

ACETYLATION; AGED; AGED, 80 AND OVER; ANILIDES; ANTINEOPLASTIC AGENTS; BENZOQUINONES; BORONIC ACIDS; CELL LINE, TUMOR; CELL SURVIVAL; DRUG SCREENING ASSAYS, ANTITUMOR; GENE EXPRESSION; HISTONE DEACETYLASE INHIBITORS; HISTONE DEACETYLASES; HISTONES; HUMANS; HYDROXAMIC ACIDS; INDOLES; INHIBITORY CONCENTRATION 50; LACTAMS, MACROCYCLIC; MIDDLE AGED; PROTEIN PROCESSING, POST-TRANSLATIONAL; PYRAZINES; URINARY BLADDER NEOPLASMS; UROTHELIUM;

EID: 84901698457     PISSN: 15384047     EISSN: 15558576     Source Type: Journal    
DOI: 10.4161/cbt.28469     Document Type: Article

References (69)

1. von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005; 23:4602-8; PMID:16034041; http://dx.doi.org/10.1200/JCO.2005.07.757
2. Sternberg CN, Bellmunt J, Sonpavde G, Siefker-Radtke AO, Stadler WM, Bajorin DF, Dreicer R, George DJ, Milowsky MI, Theodorescu D, et al.; International Consultation on Urologic Disease-European Association of Urology Consultation on Bladder Cancer 2012. ICUD-EAU International Consultation on Bladder Cancer 2012: Chemotherapy for urothelial carcinoma-neoadjuvant and adjuvant settings. Eur Urol 2013; 63:58-66; PMID:22917984; http://dx.doi.org/10. 1016/j.eururo.2012.08.010
3. Butler JS, Koutelou E, Schibler AC, Dent SY. Histone-modifying enzymes: regulators of developmental decisions and drivers of human disease. Epigenomics 2012; 4:163-77; PMID:22449188; http://dx.doi.org/10.2217/epi.12.3
4. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell 2012; 150:12-27; PMID:22770212; http://dx.doi.org/10.1016/j.cell.2012.06. 013
5. Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S, Wu R, Chen C, Li X, Zhou L, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet 2011; 43:875-8; PMID:21822268; http://dx.doi.org/10.1038/ng.907
6. Ahmad M, Hamid A, Hussain A, Majeed R, Qurishi Y, Bhat JA, Najar RA, Qazi AK, Zargar MA, Singh SK, et al. Understanding histone deacetylases in the cancer development and treatment: an epigenetic perspective of cancer chemotherapy. DNA Cell Biol 2012; 31(Suppl 1):S62-71; PMID:22462686; http://dx.doi.org/10.1089/dna.2011.1575
7. Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 2001; 1:194-202; PMID:11902574; http://dx.doi.org/10.1038/35106079
8. Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 2003; 115:727-38; PMID:14675537; http://dx.doi.org/10.1016/S0092-8674(03)00939-5
9. Li Y, Shin D, Kwon SH. Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes. FEBS J 2013; 280:775-93; PMID:23181831
10. Boyault C, Sadoul K, Pabion M, Khochbin S. HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene 2007; 26:5468-76; PMID:17694087; http://dx.doi.org/10.1038/sj.onc. 1210614
11. Bazzaro M, Lin Z, Santillan A, Lee MK, Wang MC, Chan KC, Bristow RE, Mazitschek R, Bradner J, Roden RB. Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor. Clin Cancer Res 2008; 14:7340-7; PMID:19010849; http://dx.doi.org/10. 1158/1078-0432.CCR-08-0642
12. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P, et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 2005; 280:26729-34; PMID:15937340; http://dx.doi.org/10.1074/jbc.C500186200
13. Karkoulis PK, Stravopodis DJ, Margaritis LH, Voutsinas GE. 17-Allylamino-17-demethoxygeldanamycin induces downregulation of critical Hsp90 protein clients and results in cell cycle arrest and apoptosis of human urinary bladder cancer cells. BMC Cancer 2010; 10:481; PMID:20828379; http://dx.doi.org/10.1186/1471-2407-10-481
14. Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, Chiao JH, Reilly JF, Ricker JL, Richon VM, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007; 109:31-9; PMID:16960145; http://dx.doi.org/10.1182/blood- 2006-06-025999
15. Luu TH, Morgan RJ, Leong L, Lim D, McNamara M, Portnow J, Frankel P, Smith DD, Doroshow JH, Wong C, et al. A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. Clin Cancer Res 2008; 14:7138-42; PMID:18981013; http://dx.doi.org/10.1158/1078-0432.CCR-08-0122
16. Kapoor S. Inhibition of HDAC6-dependent carcinogenesis: emerging, new therapeutic options besides belinostat. Int J Cancer 2009; 124:509; PMID:18942705; http://dx.doi.org/10.1002/ijc.23975
17. Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP. Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J Am Chem Soc 2010; 132:10842-6; PMID:20614936; http://dx.doi.org/10.1021/ja102758v
18. Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci U S A 2003; 100:4389-94; PMID:12677000; http://dx.doi.org/10.1073/pnas.0430973100
19. Scott GK, Marx C, Berger CE, Saunders LR, Verdin E, Schäfer S, Jung M, Benz CC. Destabilization of ERBB2 transcripts by targeting 3′ untranslated region messenger RNA associated HuR and histone deacetylase-6. Mol Cancer Res 2008; 6:1250-8; PMID:18644987; http://dx.doi.org/10.1158/1541-7786. MCR-07-2110
20. Niegisch G, Knievel J, Koch A, Hader C, Fischer U, Albers P, Schulz WA. Changes in histone deacetylase (HDAC) expression patterns and activity of HDAC inhibitors in urothelial cancers. Urol Oncol 2013; 31:1770-9; PMID:22944197; http://dx.doi.org/10.1016/j.urolonc.2012.06.015
21. Garg M, Kanojia D, Seth A, Kumar R, Gupta A, Surolia A, Suri A. Heat-shock protein 70-2 (HSP70-2) expression in bladder urothelial carcinoma is associated with tumour progression and promotes migration and invasion. Eur J Cancer 2010; 46:207-15; PMID:19914824; http://dx.doi.org/10.1016/j.ejca.2009.10. 020
22. Yu HJ, Chang YH, Pan CC. Prognostic significance of heat shock proteins in urothelial carcinoma of the urinary bladder. Histopathology 2013; 62:788-98; PMID:23425286; http://dx.doi.org/10.1111/his.12087
23. Namdar M, Perez G, Ngo L, Marks PA. Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents. Proc Natl Acad Sci U S A 2010; 107:20003-8; PMID:21037108; http://dx.doi.org/10.1073/pnas.1013754107
24. Lee J-H, Mahendran A, Yao Y, Ngo L, Venta-Perez G, Choy ML, Kim N, Ham W-S, Breslow R, Marks PA. Development of a histone deacetylase 6 inhibitor and its biological effects. Proc Natl Acad Sci U S A 2013; 110:15704-9; PMID:24023063; http://dx.doi.org/10.1073/pnas.1313893110
25. Modesitt SC, Sill M, Hoffman JS, Bender DP; Gynecologic Oncology Group. 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; 109:182-6; PMID:18295319; http://dx.doi.org/10.1016/ j.ygyno.2008.01.009
26. Arsenault D, Brochu-Gaudreau K, Charbonneau M, Dubois CM. HDAC6 deacetylase activity is required for hypoxia-induced invadopodia formation and cell invasion. PLoS One 2013; 8:e55529; PMID:23405166; http://dx.doi.org/10. 1371/journal.pone.0055529
27. Ding G, Liu HD, Huang Q, Liang HX, Ding ZH, Liao ZJ, Huang G. HDAC6 promotes hepatocellular carcinoma progression by inhibiting P53 transcriptional activity. FEBS Lett 2013; 587:880-6; PMID:23402884; http://dx.doi.org/10.1016/j. febslet.2013.02.001
28. Park SY, Jun JA, Jeong KJ, Heo HJ, Sohn JS, Lee HY, Park CG, Kang J. Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer. Oncol Rep 2011; 25:1677-81; PMID:21455583
29. Zhang Z, Yamashita H, Toyama T, Sugiura H, Omoto Y, Ando Y, Mita K, Hamaguchi M, Hayashi S, Iwase H. HDAC6 expression is correlated with better survival in breast cancer. Clin Cancer Res 2004; 10:6962-8; PMID:15501975; http://dx.doi.org/10.1158/1078-0432.CCR-04-0455
30. Sakuma T, Uzawa K, Onda T, Shiiba M, Yokoe H, Shibahara T, Tanzawa H. Aberrant expression of histone deacetylase 6 in oral squamous cell carcinoma. Int J Oncol 2006; 29:117-24; PMID:16773191
31. Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, Craddock C, Turner BM. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia 2005; 19:1751-9; PMID:16121216; http://dx.doi.org/10.1038/sj.leu.2403910
32. Lee JS, Leem SH, Lee SY, Kim SC, Park ES, Kim SB, Kim SK, Kim YJ, Kim WJ, Chu IS. Expression signature of E2F1 and its associated genes predict superficial to invasive progression of bladder tumors. J Clin Oncol 2010; 28:2660-7; PMID:20421545; http://dx.doi.org/10.1200/JCO.2009.25.0977
33. Dyrskjøt L, Kruhøffer M, Thykjaer T, Marcussen N, Jensen JL, Møller K, Ørntoft TF. Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res 2004; 64:4040-8; PMID:15173019; http://dx.doi.org/10.1158/0008-5472.CAN-03-3620
34. Dyrskjot L, Zieger K, Orntoft TF. Recent advances in high-throughput molecular marker identification for superficial and invasive bladder cancers. Front Biosci 2007; 12:2063-73; PMID:17127444; http://dx.doi.org/10.2741/2211
35. Mengual L, Burset M, Ars E, Lozano JJ, Villavicencio H, Ribal MJ, Alcaraz A. DNA microarray expression profiling of bladder cancer allows identification of noninvasive diagnostic markers. J Urol 2009; 182:741-8; PMID:19539325; http://dx.doi.org/10.1016/j.juro.2009.03.084
36. Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C. Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol 2006; 24:778-89; PMID:16432078; http://dx.doi.org/10.1200/JCO.2005.03.2375
37. Kanno K, Kanno S, Nitta H, Uesugi N, Sugai T, Masuda T, Wakabayashi G, Maesawa C. Overexpression of histone deacetylase 6 contributes to accelerated migration and invasion activity of hepatocellular carcinoma cells. Oncol Rep 2012; 28:867-73; PMID:22766642
38. Jung KH, Noh JH, Kim JK, Eun JW, Bae HJ, Chang YG, Kim MG, Park WS, Lee JY, Lee SY, et al. Histone deacetylase 6 functions as a tumor suppressor by activating c-Jun NH2-terminal kinase-mediated beclin 1-dependent autophagic cell death in liver cancer. Hepatology 2012; 56:644-57; PMID:22392728; http://dx.doi.org/10.1002/hep.25699
39. Simon D, Laloo B, Barillot M, Barnetche T, Blanchard C, Rooryck C, Marche M, Burgelin I, Coupry I, Chassaing N, et al. A mutation in the 3′-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia. Hum Mol Genet 2010; 19:2015-27; PMID:20181727; http://dx.doi.org/10.1093/hmg/ddq083
40. Chen Y, Sawyers CL, Scher HI. Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 2008; 8:440-8; PMID:18674639; http://dx.doi.org/10.1016/j.coph.2008.07.005
41. Riolo MT, Cooper ZA, Holloway MP, Cheng Y, Bianchi C, Yakirevich E, Ma L, Chin YE, Altura RA. Histone deacetylase 6 (HDAC6) deacetylates survivin for its nuclear export in breast cancer. J Biol Chem 2012; 287:10885-93; PMID:22334690; http://dx.doi.org/10.1074/jbc.M111.308791
42. Kaluza D, Kroll J, Gesierich S, Yao TP, Boon RA, Hergenreider E, Tjwa M, Rössig L, Seto E, Augustin HG, et al. Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin. EMBO J 2011; 30:4142-56; PMID:21847094; http://dx.doi.org/10.1038/emboj.2011.298
43. Lafarga V, Aymerich I, Tapia O, Mayor F Jr., Penela P. A novel GRK2/HDAC6 interaction modulates cell spreading and motility. EMBO J 2012; 31:856-69; PMID:22193721; http://dx.doi.org/10.1038/emboj.2011.466
44. Liu Y, Peng L, Seto E, Huang S, Qiu Y. Modulation of histone deacetylase 6 (HDAC6) nuclear import and tubulin deacetylase activity through acetylation. J Biol Chem 2012; 287:29168-74; PMID:22778253; http://dx.doi.org/10.1074/jbc. M112.371120
45. Oehme I, Lodrini M, Brady NR, Witt O. Histone deacetylase 10-promoted autophagy as a druggable point of interference to improve the treatment response of advanced neuroblastomas. Autophagy 2013; 9:2163-5; PMID:24145760; http://dx.doi.org/10.4161/auto.26450
46. Song C, Zhu S, Wu C, Kang J. Histone deacetylase (HDAC) 10 suppresses cervical cancer metastasis through inhibition of matrix metalloproteinase (MMP) 2 and 9 expression. J Biol Chem 2013; 288:28021-33; PMID:23897811; http://dx.doi.org/10.1074/jbc.M113.498758
47. Van Damme M, Crompot E, Meuleman N, Mineur P, Bron D, Lagneaux L, Stamatopoulos B. HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance. Epigenetics 2012; 7:1403-12; PMID:23108383; http://dx.doi.org/10.4161/epi.22674
48. Wilting RH, Yanover E, Heideman MR, Jacobs H, Horner J, van der Torre J, DePinho RA, Dannenberg JH. Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis. EMBO J 2010; 29:2586-97; PMID:20571512; http://dx.doi.org/10.1038/emboj.2010.136
49. Oehme I, Linke JP, Böck BC, Milde T, Lodrini M, Hartenstein B, Wiegand I, Eckert C, Roth W, Kool M, et al. Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc Natl Acad Sci U S A 2013; 110:E2592-601; PMID:23801752; http://dx.doi.org/10.1073/pnas.1300113110
50. Hackanson B, Rimmele L, Benkißer M, Abdelkarim M, Fliegauf M, Jung M, Lübbert M. HDAC6 as a target for antileukemic drugs in acute myeloid leukemia. Leuk Res 2012; 36:1055-62; PMID:22464548; http://dx.doi.org/10.1016/j. leukres.2012.02.026
51. Kaliszczak M, Trousil S, Åberg O, Perumal M, Nguyen QD, Aboagye EO. A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth. Br J Cancer 2013; 108:342-50; PMID:23322205; http://dx.doi.org/ 10.1038/bjc.2012.576
52. Qin HX, Cui HK, Pan Y, Yang J, Ren YF, Hua CH, Hua FF, Qiao YH. HDAC6 siRNA inhibits proliferation and induces apoptosis of HeLa cells and its related molecular mechanism. Asian Pac J Cancer Prev 2012; 13:3367-71; PMID:22994762; http://dx.doi.org/10.7314/APJCP.2012.13.7.3367
53. Subramanian C, Jarzembowski JA, Opipari AW Jr., Castle VP, Kwok RP. HDAC6 deacetylates Ku70 and regulates Ku70-Bax binding in neuroblastoma. Neoplasia 2011; 13:726-34; PMID:21847364
54. Zuo Q, Wu W, Li X, Zhao L, Chen W. HDAC6 and SIRT2 promote bladder cancer cell migration and invasion by targeting cortactin. Oncol Rep 2012; 27:819-24; PMID:22089141
55. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang X-F, Yao T-P. HDAC6 is a microtubule-associated deacetylase. Nature 2002; 417:455-8; PMID:12024216; http://dx.doi.org/10.1038/417455a
56. Cabrero JR, Serrador JM, Barreiro O, Mittelbrunn M, Naranjo-Suárez S, Martín-Cófreces N, Vicente-Manzanares M, Mazitschek R, Bradner JE, Ávila J, et al. Lymphocyte chemotaxis is regulated by histone deacetylase 6, independently of its deacetylase activity. Mol Biol Cell 2006; 17:3435-45; PMID:16738306; http://dx.doi.org/10.1091/mbc.E06-01-0008
57. Valenzuela-Fernández A, Cabrero JR, Serrador JM, Sánchez-Madrid F. HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions. Trends Cell Biol 2008; 18:291-7; PMID:18472263; http://dx.doi.org/10.1016/j.tcb.2008.04.003
58. Gao YS, Hubbert CC, Lu J, Lee YS, Lee JY, Yao TP. Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis. Mol Cell Biol 2007; 27:8637-47; PMID:17938201; http://dx.doi.org/10.1128/MCB.00393-07
59. Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, Anderson KC. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A 2005; 102:8567-72; PMID:15937109; http://dx.doi.org/10.1073/pnas.0503221102
60. Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Andtbacka RH, Dunner K Jr., Pal A, Bornmann WG, Chiao PJ, Huang P, et al. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 2006; 66:3773-81; PMID:16585204; http://dx.doi.org/10.1158/0008-5472. CAN-05-2961
61. Boyault C, Zhang Y, Fritah S, Caron C, Gilquin B, Kwon SH, Garrido C, Yao TP, Vourc'h C, Matthias P, et al. HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev 2007; 21:2172-81; PMID:17785525; http://dx.doi.org/10.1101/gad.436407
62. Santo L, Hideshima T, Kung AL, Tseng JC, Tamang D, Yang M, Jarpe M, van Duzer JH, Mazitschek R, Ogier WC, et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 2012; 119:2579-89; PMID:22262760; http://dx.doi.org/10.1182/blood-2011-10-387365
63. Rao R, Fiskus W, Yang Y, Lee P, Joshi R, Fernandez P, Mandawat A, Atadja P, Bradner JE, Bhalla K. HDAC6 inhibition enhances 17-AAG - mediated abrogation of hsp90 chaperone function in human leukemia cells. Blood 2008; 112:1886-93; PMID:18591380; http://dx.doi.org/10.1182/blood-2008-03-143644
64. Komatsu S, Moriya S, Che XF, Yokoyama T, Kohno N, Miyazawa K. Combined treatment with SAHA, bortezomib, and clarithromycin for concomitant targeting of aggresome formation and intracellular proteolytic pathways enhances ER stress-mediated cell death in breast cancer cells. Biochem Biophys Res Commun 2013; 437:41-7; PMID:23792097; http://dx.doi.org/10.1016/j.bbrc.2013.06.032
65. Hoffmann MJ, Florl AR, Seifert HH, Schulz WA. Multiple mechanisms downregulate CDKN1C in human bladder cancer. Int J Cancer 2005; 114:406-13; PMID:15551363; http://dx.doi.org/10.1002/ijc.20749
66. Koch A, Hatina J, Rieder H, Seifert HH, Huckenbeck W, Jankowiak F, Florl AR, Stoehr R, Schulz WA. Discovery of TP53 splice variants in two novel papillary urothelial cancer cell lines. Cell Oncol (Dordr) 2012; 35:243-57; PMID:22669776; http://dx.doi.org/10.1007/s13402-012-0082-8
67. Swiatkowski S, Seifert HH, Steinhoff C, Prior A, Thievessen I, Schliess F, Schulz WA. Activities of MAP-kinase pathways in normal uroepithelial cells and urothelial carcinoma cell lines. Exp Cell Res 2003; 282:48-57; PMID:12490193; http://dx.doi.org/10.1006/excr.2002.5647
68. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 1991; 139:271-9; PMID:1710634; http://dx.doi.org/10.1016/0022-1759(91)90198-O
69. Shechter D, Dormann HL, Allis CD, Hake SB. Extraction, purification and analysis of histones. Nat Protoc 2007; 2:1445-57; PMID:17545981; http://dx.doi.org/10.1038/nprot.2007.202