title: Histone deacetylase 6 represents a novel drug target in the oncogenic Hedgehog signaling pathway.
abstract: Uncontrolled Hedgehog (Hh) signaling is the cause of several malignancies, including the pediatric cancer medulloblastoma, a neuroectodermal tumor affecting the cerebellum. Despite the development of potent Hh pathway antagonists, medulloblastoma drug resistance is still an unresolved issue that requires the identification of novel drug targets. Following up on our observation that histone deacetylase 6 (HDAC6) expression was increased in Hh-driven medulloblastoma, we found that this enzyme is essential for full Hh pathway activation. Intriguingly, these stimulatory effects of HDAC6 are partly integrated downstream of primary cilia, a known HDAC6-regulated structure. In addition, HDAC6 is also required for the complete repression of basal Hh target gene expression. These contrasting effects are mediated by HDAC6's impact on Gli2 mRNA and GLI3 protein expression. As a result of this complex interaction with Hh signaling, global transcriptome analysis revealed that HDAC6 regulates only a subset of Smoothened- and Gli-driven genes, including all well-established Hh targets such as Ptch1 or Gli1. Importantly, medulloblastoma cell survival was severely compromised by HDAC6 inhibition in vitro and pharmacologic HDAC6 blockade strongly reduced tumor growth in an in vivo allograft model. In summary, our data describe an important role for HDAC6 in regulating the mammalian Hh pathway and encourage further studies focusing on HDAC6 as a novel drug target in medulloblastoma.
authors.affiliation: Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Marburg, Germany.
authors.forename: Pavan Kumar
authors.initials: PK
authors.lastname: Dhanyamraju
authors.affiliation: Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Marburg, Germany.
authors.forename: Philipp Simon
authors.initials: PS
authors.lastname: Holz
authors.affiliation: Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Marburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Finkernagel
authors.affiliation: Department of Surgery, Philipps University, Marburg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Fendrich
authors.affiliation: Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Marburg, Germany. lauth@imt.uni-marburg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lauth
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D053823:Hedgehog Proteins / Q000235:genetics*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008527:Medulloblastoma / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases