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Cited by 116Histone Deacetylase Inhibitors ResearchProstate Cancer Treatment and ResearchAngiogenesis and VEGF in Cancer

Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment

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Isaacs, John T., Antony, Lizamma, Dalrymple, Susan L., Brennen, W. Nathaniel, Gerber, Stephanie, Hammers, Hans, Wissing, Michel, Kachhap, Sushant +6 more·2013·Cancer Research
DOI 10.1158/0008-5472.can-12-2730PMC PMC3578133

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Abstract

Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10–30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1α, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386–99. ©2012 AACR.

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  • Tasquinimod is a small-molecule compound that binds to HDAC4 and is believed to inhibit the transcription of downstream target genes by inhibiting the formation of HDAC3/N-CoR complexes.

    “Tasquinimod is a small-molecule compound that binds to HDAC4 and is believed to inhibit the transcription of downstream target genes by inhibiting the formation of HDAC3/N-CoR complexes39.”

    From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [39]

    The Results sections on allosteric binding and complex formation report that tasquinimod binds HDAC4 and prevents its association with N-CoR/HDAC3. The paper links this mechanism to reduced HIF-1-dependent transcription, but does not support a general inhibition of downstream gene transcription: it also says HDAC3 represses transcription associated with most HDAC4 client transcription factors. Page numbers are unavailable in our copy. (LLM, conf=0.84)

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Research works printed but not linked: 44

  1. [2]Isaacs JT The long and winding road for the development of tasquinimod as an oral second-generation quinoline-3-carboxamide antiangiogenic drug for the treatment of prostate cancer Expert Opin Investig Drugs 2010 19 1235 1243 PMC4124623 20836618
  2. [3]Isaacs JT Pili R Qian DZ Dalrymple SL Garrison JB Kyprianou N Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer Prostate 2006 66 1768 1778 16955399
  3. [4]Dalrymple SL Becker RE Isaacs JT The quinoline-3-carboxamide anti-angiogenic agent, tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts Prostate 2007 67 790 797 17373719
  4. [5]Olsson A Bjork A Vallon-Christersson J Isaacs JT Leanderson T Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors Mol Cancer 2010 9 107 20470445 PMC2885345
  5. [6]Dalrymple SL Becker RE Zhou H DeWeese TL Isaacs JT Tasquinimod Prevents the Angiogenic Rebound Induced by Fractionated Radiation Resulting in an Enhanced Therapeutic Response of Prostate Cancer Xenografts Prostate 2012 72 638 648 21837778 PMC4086682
  6. [7]Kallberg E Vogl T Liberg D Olsson A Bjork P Wilkstrom P S100A9 interaction with TLR4 promotes tumor growth PLoS ONE 2012 7 e34207 22470535 PMC3314596
  7. [8]Lunt SJ Chaudary N Hill RP The tumor microenvironment and metastatic disease Clin Exp Metastasis 2009 26 19 34 18543068
  8. [9]Hanahan D Folkman J Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis Cell 1996 86 353 364 8756718
  9. [10]Jennbacken K Welen K Olsson A Axelsson B Torngren M Damber JE Inhibition of metastasis in a castration resistant prostate cancer model by quinoline-3-carboxamide tasquinimod (ABR-215050) Prostate 2012 72 913 924 22287276
  10. [11]Nakatsu MN Sainson RC Aoto JN Aikenhead M Perez-del-Pulgar S Carpenter PM Angiogenic sprouting and capillary lumen formation modeled by human umbilical vein endothetial cells (HUVEC) in fibrin gels: the role of fibroblasts and Angiopoietin-1 Microvasc Res 2003 66 102 112 12935768
  11. [12]Denmeade SR Mhaka AM Rosen DM Brennen WN Dalrymple S Dach I Engineering a Prostate-specific Membrane Antigen–Activated Tumor Endothelial Cell Prodrug for Cancer Therapy Science Trans Med 2012 4 140 154 PMC3715055 22745436
  12. [13]Litvinov IV Vander Griend DJ Xu Y Antony L Dalrymple SL Isaacs JT Lowcalcium serum-free defined medium selects for growth of normal prostatic epithelial stem cells Cancer Res 2006 66 8598 8607 16951173 PMC4124600
  13. [16]Bjork P Bjork A Vogl T Stenstrom M Liberg D Olsson A Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides PLoS Biol 2009 7 e97 19402754 PMC2671563
  14. [17]Bottomley MJ Surdo PL Di Giovine P Cirillo A Scarpelli R Ferrigno F Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain J Biol Chem 2008 283 26694 26704 18614528 PMC3258910
  15. [18]Raman V Artemov D Pathak AP Winnard PT McNutt S Yudina A Characterizing vascular parameters in hypoxic regions: a combination magnetic resonance and optical imaging study of a human prostate cancer model Cancer Res 2006 66 9929 9936 17047055
  16. [19]Semenza GL Jiang BH Leung SW Passantino R Concordet JP Maire P Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1 J Biol Chem 1996 271 32529 32537 8955077
  17. [20]Prakash K Pirozzi G Elashoff M Munger W Waga I Dhir R Symptomatic and asymptomatic benign prostatic hyperplasia: molecular differentiation by using microarrays Proc Natl Acad Sci U S A 2002 99 7598 7603 12032329 PMC124296
  18. [21]Liu W Laitinen S Vihinen M Kowalski J Yu G Chen L Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer Nat Med 2009 15 559 565 19363497 PMC2839160
  19. [22]Dunn TA Chen S Faith DA Hicks JL Platz EA Chen Y A novel role of myosin VI in human prostate cancer Am J Pathol 2006 169 1843 1854 17071605 PMC1780223
  20. [23]Denko N Wernke-Dollries K Johnson AB Hammond E Chiang CM Barton MC Hypoxia actively represses transcription by inducing negative cofactor 2 (Dr1/DrAP1) and blocking preinitiation complex assembly J Biol Chem 2003 278 5744 5749 12477712
  21. [25]Johnson AB Denko N Barton MC Hypoxia induces a novel signature of chromatin modifications and global repression of transcription Mut Res 2008 640 174 179 18294659 PMC2346607
  22. [26]Li Q Costa M c-Myc mediates a hypoxia-induced decrease in acetylated histone H4 Biochimie 2009 91 1307 1310 19596041 PMC2749254
  23. [27]Haberland M Montgomery RL Olson ER The many roles of histone deacetylases in development and physiology: implications for disease and therapy Nat Rev/Genet 2009 10 32 42 PMC3215088 19065135
  24. [28]Halkidou K Cook S Leung HY Neal DE Robson CN Nuclear accumulation of histone deacetylase 4 (HDAC4) coincides with the loss of androgen sensitivity in hormone refractory cancer of the prostate Eur Urol 2004 45 382 389 15036687
  25. [29]Cadot B Brunetti M Coppari S Fedeli S de Rinaldis E Dello Russo C Loss of histone deacetylase 4 causes segregation defects during mitosis of p53-deficient human tumor cells Cancer Res 2009 69 6074 6082 19622775
  26. [30]Geng H Harvey CT Pittsenbarger J Liu Q Beer TM Xue C HDAC4 protein regulates HIF-1α protein lysine acetylation and cancer cell response to hypoxia J Biol Chem 2011 286 38095 38102 21917920 PMC3207467
  27. [31]Martin M Kettmann R Dequiedt F Class IIa histone deacetylases: regulating the regulators Oncogene 2007 26 5450 5467 17694086
  28. [32]Kato H Tamamizu-Kato S Shibasaki F Histone Deacetylase 7 associates with hypoxia-induced factor-1α and increases transcriptional activity J Biol Chem 2004 279 41966 41974 15280364
  29. [33]Ellis L Hammers H Pili R Targeting tumor angiogenesis with histone deacetylase inhibitors Cancer Lett 2009 280 145 153 19111391 PMC2814368
  30. [34]Seo HW Kim EJ Na H Lee MO Transcriptional activation of hypoxia-inducible factor-1 alpha by HDAC4 and HDAC5 involves differential recruitment of p300 and FIH-1 FEBS Lett 2009 583 55 60 19071119
  31. [35]Xenaki G Ontikatze T Rajendran R Stratford IJ Dive C Krstic-Demonacos M PCAF is an HIF-1α cofactor that regulates p53 transcriptional activity in hypoxia Oncogene 2008 27 5785 5796 18574470 PMC2664615
  32. [36]Lim JH Lee YM Chun YS Chen J Kim JE Park JW Sirtuin 1 modulates cellular responses to hypoxia by deacetylating Hypoxia-Induced Factor 1α Mol Cell 2010 38 864 878 20620956
  33. [37]Michel G Minet E Mottet D Remacle J Michiels C Site-directed mutagenesis of the hypoxia-induced factor-1α DNA-binding domain Biochim Biophys Acta 2002 1578 73 83 12393189
  34. [38]Richard DE Berra E Gothie E Roux D Pouyssegur J p42/p44 Mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1α (HIF-1α) and enhance the transcriptional activity of HIF-1α J Biol Chem 1999 274 32631 32637 10551817
  35. [39]Liu R Wang L Chen G Katoh H Chen C Liu Y FOXP3 up-regulates p21 expression by site-specific inhibition of histone deacetylase 2/ histone deacetylatase 4 association to the locus Cancer Res 2009 69 2252 2259 19276356 PMC2715174
  36. [40]Mottet D Pirotte S Lamour V Hagedorn M Javerzat S Bikfalvi A HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism Oncogene 2009 28 243 256 18850004
  37. [41]Baumeister P Dong D Fu Y Lee AS Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis Mol Cancer Ther 2009 8 1086 1094 19417144 PMC2889001
  38. [42]Halili M Andrews MR Labzin LI Schroder K Matthias G Cao C Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like receptor 4 agonist LPS J Leukoc Biol 2010 87 1103 1114 20200406
  39. [43]Wang X Li G Wang A Zan Z Merchan JR Halmos B Combined histone deacetylase and cyclooxigenase inhibition achieves enhanced antiangiogenic effects in lung cancer cells Mol Carcinogenesis 2012 (In press) PMC3980866 22121107
  40. [44]Urbich C Rossig L Kaluza D Potent M Boeckel JN Knau A Hdac5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells Blood 2009 113 5669 5679 19351956
  41. [46]Chu F Chou P Mirkin BL Mousa SA Rebbaa A Cellular conditioning with trichostatin A enhances the anti-stress response through up-regulation of HDAC4 and down-regulation of the IGF/Akt pathway Aging Cell 2008 7 516 525 18489729 PMC2574770
  42. [47]Zhao F Hoechst B Duffy A Gamrekelashvili J Fiorvanti S Manns MP S100A9 a new marker for monocytic human myeloid-derived suppressor cells Immunology 2012 136 176 183 22304731 PMC3403264
  43. [48]Bunt SK Clements VK Hanson EM Sinha P Ostrand-Rosenberg S Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through Toll-like receptor 4 J Leukoc Biol 2009 85 996 1004 19261929 PMC2698586
  44. [50]Squadrito ML De Palma M Macrophage regulation of tumor angiogenesis: implications for cancer therapy Mol Aspects Med 2011 32 123 145 21565215

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Authors
Isaacs, J. T., Antony, L., Dalrymple, S. L., Brennen, W. N., Gerber, S., Hammers, H., Wissing, M., Kachhap, S., Luo, J., Xing, L., Björk, P., Olsson, A., Björk, A., & Leanderson, T.
Affiliations
Johns Hopkins University (US)
Corresponding author
Isaacs, John T.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2013-02-14
Volume
73
Issue
4
Pages
1386-1399
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-12-2730
PMC
PMC3578133
OpenAlex
W2129927282
Cited by
116
References
5
Citations by year
2026: 10 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 7 · 2021: 12 · 2020: 7 · 2019: 4 · 2018: 7 · 2017: 3 · 2016: 8 · 2015: 11 · 2014: 11 · 2013: 10
FWCI
4.12
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Cancer Research Institute
  • Gladstone Institutes
  • National Cancer Institute (P50CA058236, P30CA006973)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
tasquinimod, HDAC4, allosteric modulation, antiangiogenic drugs, castration-resistant prostate cancer, zinc-binding domain, epigenetic reprogramming, tumor microenvironment, tumor endothelial cells, drug target identification
MeSH terms
Acetylation, Allosteric Regulation, Animals, Cell Survival, Histone Deacetylases, Histones, Humans, Mice, Nude, Models, Molecular, Neoplasms, Prodrugs, Protein Binding, Quinolines, Repressor Proteins, Blotting, Western, Quinolones, Signal Transduction, Cell Hypoxia, Protein Structure, Tertiary, Thapsigargin, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Tumor Microenvironment, Human Umbilical Vein Endothelial Cells

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