Characterization of a New Small-molecule Inhibitor of HDAC6 in Glioblastoma

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2020 Jun 4

PMID 32488056

Citations 17

Authors

Jaione Auzmendi-Iriarte

Ander Saenz-Antonanzas

Idoia Mikelez-Alonso

Estefania Carrasco-Garcia

Maitena Tellaetxe-Abete

Charles H Lawrie

Nicolas Sampron

Aitziber L Cortajarena

Ander Matheu

Affiliations

Soon will be listed here.

Abstract

Histone deacetylase 6 (HDAC6) is an epigenetic modifier that is an attractive pharmacological target in cancer. In this work, we show that HDAC6 is elevated in glioblastoma, the most malignant and common brain tumor in adults, in which its high levels correlate with poor patient survival and is more abundant in glioma stem cell subpopulation. Moreover, we identified a new small-molecule inhibitor of HDAC6, which presents strong sensitivity for HDAC6 inhibition and exerts high cytotoxic activity, alone or in combination with temozolomide. It is also able to significantly reduce tumor growth in vivo. Transcriptomic analysis of patient-derived glioma stem cells revealed an increase in cell differentiation and cell death pathways, as well as a decrease in cell-cycle activity and cell division by the treatment with the compound. Finally, the comparison with a pan-HDAC inhibitor, Vorinostat (SAHA), or HDAC6-specific inhibitor, Tubastatin A, showed higher target specificity and antitumor activity of the new HDAC6 inhibitor. In conclusion, our data reveal the efficacy of a novel HDAC6 inhibitor in glioblastoma preclinical setting.

Citing Articles

HDAC6 inhibition through WT161 synergizes with temozolomide, induces apoptosis, reduces cell motility, and decreases β-catenin levels in glioblastoma cells.

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Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.

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Chemical Versatility in Catalysis and Inhibition of the Class IIb Histone Deacetylases.

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References

Louis D, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee W . The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016; 131(6):803-20. DOI: 10.1007/s00401-016-1545-1. View

Ostrom Q, Bauchet L, Davis F, Deltour I, Fisher J, Langer C . The epidemiology of glioma in adults: a "state of the science" review. Neuro Oncol. 2014; 16(7):896-913. PMC: 4057143. DOI: 10.1093/neuonc/nou087. View

Stupp R, Mason W, van den Bent M, Weller M, Fisher B, Taphoorn M . Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):987-96. DOI: 10.1056/NEJMoa043330. View

Brennan C, Verhaak R, McKenna A, Campos B, Noushmehr H, Salama S . The somatic genomic landscape of glioblastoma. Cell. 2013; 155(2):462-77. PMC: 3910500. DOI: 10.1016/j.cell.2013.09.034. View

Patel A, Tirosh I, Trombetta J, Shalek A, Gillespie S, Wakimoto H . Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014; 344(6190):1396-401. PMC: 4123637. DOI: 10.1126/science.1254257. View

van Tellingen O, Yetkin-Arik B, de Gooijer M, Wesseling P, Wurdinger T, de Vries H . Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist Updat. 2015; 19:1-12. DOI: 10.1016/j.drup.2015.02.002. View

Parada L, Dirks P, Wechsler-Reya R . Brain Tumor Stem Cells Remain in Play. J Clin Oncol. 2017; 35(21):2428-2431. PMC: 5516484. DOI: 10.1200/JCO.2017.73.9540. View

Touat M, Idbaih A, Sanson M, Ligon K . Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol. 2017; 28(7):1457-1472. PMC: 5834086. DOI: 10.1093/annonc/mdx106. View

Gusyatiner O, Hegi M . Glioma epigenetics: From subclassification to novel treatment options. Semin Cancer Biol. 2017; 51:50-58. DOI: 10.1016/j.semcancer.2017.11.010. View

10.

Sturm D, Bender S, Jones D, Lichter P, Grill J, Becher O . Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer. 2014; 14(2):92-107. PMC: 4003223. DOI: 10.1038/nrc3655. View

11.

Capper D, Jones D, Sill M, Hovestadt V, Schrimpf D, Sturm D . DNA methylation-based classification of central nervous system tumours. Nature. 2018; 555(7697):469-474. PMC: 6093218. DOI: 10.1038/nature26000. View

12.

Jones P, Issa J, Baylin S . Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016; 17(10):630-41. DOI: 10.1038/nrg.2016.93. View

13.

Bezecny P . Histone deacetylase inhibitors in glioblastoma: pre-clinical and clinical experience. Med Oncol. 2014; 31(6):985. DOI: 10.1007/s12032-014-0985-5. View

14.

Seidel C, Schnekenburger M, Dicato M, Diederich M . Histone deacetylase 6 in health and disease. Epigenomics. 2015; 7(1):103-18. DOI: 10.2217/epi.14.69. View

15.

Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A . HDAC6 is a microtubule-associated deacetylase. Nature. 2002; 417(6887):455-8. DOI: 10.1038/417455a. View

16.

Barneda-Zahonero B, Parra M . Histone deacetylases and cancer. Mol Oncol. 2012; 6(6):579-89. PMC: 5528343. DOI: 10.1016/j.molonc.2012.07.003. View

17.

Zhang Y, Kwon S, Yamaguchi T, Cubizolles F, Rousseaux S, Kneissel M . Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol Cell Biol. 2008; 28(5):1688-701. PMC: 2258784. DOI: 10.1128/MCB.01154-06. View

18.

Li S, Liu X, Chen X, Zhang L, Wang X . Histone deacetylase 6 promotes growth of glioblastoma through inhibition of SMAD2 signaling. Tumour Biol. 2015; 36(12):9661-5. DOI: 10.1007/s13277-015-3747-x. View

19.

Wang Z, Hu P, Tang F, Lian H, Chen X, Zhang Y . HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma. Cancer Lett. 2016; 379(1):134-42. DOI: 10.1016/j.canlet.2016.06.001. View

20.

Perez-Salvia M, Aldaba E, Vara Y, Fabre M, Ferrer C, Masdeu C . and activity of a new small-molecule inhibitor of HDAC6 in mantle cell lymphoma. Haematologica. 2018; 103(11):e537-e540. PMC: 6278978. DOI: 10.3324/haematol.2018.189241. View