Summary:
Hedgehog signaling plays a vital role in regulating varied fundamental processes including embryonic development, proliferation, and differentiation. Aberrant hedgehog signaling has been one of the reason for cancers such as Basal cell carcinoma (BCC), rhabdomyosarcoma (RMS) and medulloblastoma (MB). Medulloblastoma, a malignant pediatric brain tumor is one such cancer. Even after the development of impressive Hh pathway antagonists, drug resistance in medulloblastoma has been one of the most waffling issues which require identification of new drug targets.
In the present study, increased histone deacetylase 6 (HDAC6) expression was observed in Hh-driven medulloblastoma and it is crucial for full Hh pathway activation. Interestingly, the stimulatory outcome/s of HDAC6 are partially integrated downstream of primary cilia, a known HDAC6-regulated structure. Further, HDAC6 is also essential for the repression of basal Hh target gene expression. These diverse outcomes are negotiated by HDAC6’s impact on Gli2 mRNA and GLI3 protein expression. As a consequence of this intricate interplay with Hh signaling, only a subset of Gli and Smoothened driven genes are regulated by HDAC6 apart from the well-known Hh targets such as Gli1 or Ptch1 which was shown by global transcriptome analysis. Overall, survival of medulloblastoma cells was critically compromised by in vitro inhibition of HDAC6 and blockade of HDAC6 pharmacologically greatly reduced tumor growth in an in vivo allograft model.
In conclusion, the data illustrates the crucial aspects of HDAC6 in regulating the Hh pathway in mammals and encourage novel studies directed towards HDAC6 as a unique drug target in medulloblastoma.
Bibliographie / References
- Chang, A., & Oro, A. (2012). Initial assessment of tumor regrowth after vismodegib in advanced basal cell carcinoma. Archives of Dermatology, 148(11), 1324-1325. https://doi.org/10.1001/archdermatol.2012.2354
- Eberhart, C. G., Kepner, J. L., Goldthwaite, P. T., Kun, L. E., Duffner, P. K., Friedman, H. S., … Burger, P. C. (2002). Histopathologic grading of medulloblastomas: A Pediatric Oncology Group study. Cancer, 94(2), 552-560. https://doi.org/10.1002/cncr.10189
- Fogarty, M. P., Kessler, J. D., & Wechsler-Reya, R. J. (2005). Morphing into cancer: The role of developmental signaling pathways in brain tumor formation. Journal of Neurobiology. https://doi.org/10.1002/neu.20166
- Ellison, D. W. (2010). Childhood medulloblastoma: Novel approaches to the classification of a heterogeneous disease. Acta Neuropathologica. https://doi.org/10.1007/s00401-010-0726-6
- Grammel, D., Warmuth-Metz, M., Von Bueren, A. O., Kool, M., Pietsch, T., Kretzschmar, H. A., … Schüller, U. (2012). Sonic hedgehog-associated medullobla stoma arising from the cochlear nuclei of the brainstem. Acta Neuropathologica, 123(4), 601-614. https://doi.org/10.1007/s00401- 012-0961-0
- Echelard, Y., Epstein, D. J., St-Jacques, B., Shen, L., Mohler, J., McMahon, J. A., & McMahon, A. P. (1993). Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell, 75(7), 1417-1430. https://doi.org/10.1016/0092- 8674(93)90627-3
- Dierks, C., Beigi, R., Guo, G.-R., Zirlik, K., Stegert, M. R., Manley, P., … Warmuth, M. (2008). Expansion of Bcr-Abl-Positive Leukemic Stem Cells Is Dependent on Hedgehog Pathway Activation. Cancer Cell, 14(3), 238-249. https://doi.org/10.1016/j.ccr.2008.08.003
- Dai, C., Whitesell, L., Rogers, A. B., & Lindquist, S. (2007). Heat Shock Factor 1 Is a Powerful Multifaceted Modifier of Carcinogenesis. Cell, 130(6), 1005-1018. https://doi.org/10.1016/j.cell.2007.07.020
- Fossati, P., Ricardi, U., & Orecchia, R. (2009). Pediatric medulloblastoma: Toxicity of current treatment and potential role of protontherapy. Cancer Treatment Reviews. https://doi.org/10.1016/j.ctrv.2008.09.002
- Clement, V., Sanchez, P., de Tribolet, N., Radovanovic, I., & Ruiz i Altaba, A. (2007). HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Current Biology : CB, 17(2), 165-72. https://doi.org/10.1016/j.cub.2006.11.033
- Berbari, N. F., O'Connor, A. K., Haycraft, C. J., & Yoder, B. K. (2009). The Primary Cilium as a Complex Signaling Center. Current Biology. https://doi.org/10.1016/j.cub.2009.05.025
- Homolog Kif7 Plays an Essential Role in Modulating Hh Signal Transduction during Development. Current Biology, 19(15), 1320- 1326. https://doi.org/10.1016/j.cub.2009.06.046
- Cebotaru, L., Liu, Q., Yanda, M. K., Boinot, C., Outeda, P., Huso, D. L., … Cebotaru, V. (2016). Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease. Kidney International, 90(1), 90-99. https://doi.org/10.1016/j.kint.2016.01.026
- Ferguson, B. S., & McKinsey, T. A. (2015). Non-sirtuin histone deacetylases in the control of cardiac aging. Journal of Molecular and Cellular Cardiology. https://doi.org/10.1016/j.yjmcc.2015.03.010
- Burke, R., Nellen, D., Bellotto, M., Hafen, E., Senti, K. a, Dickson, B. J., & Basler, K. (1999). Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell, 99(7), 803-815. https://doi.org/10.1016/S0092- 8674(00)81677-3
- Caspary, T., García-García, M. J., Huangfu, D., Eggenschwiler, J. T., Wyler, M. R., Rakeman, A. S., … Anderson, K. V. (2002). Mouse Dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Current Biology, 12(18), 1628-1632. https://doi.org/10.1016/S0960- 9822(02)01147-8
- Inks, E. S., Josey, B. J., Jesinkey, S. R., & Chou, C. J. (2012). A novel class of small molecule inhibitors of HDAC6. ACS Chem Biol. https://doi.org/10.1021/cb200134p
- Itoh, Y., Suzuki, T., Kouketsu, A., Suzuki, N., Maeda, S., Yoshida, M., … Miyata, N. (2007). SAR Novel Series of Histone Deacetylase 6- Selective Inhibitors. J. Med. Chem., 50(22), 5425-5438. Retrieved from http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/jm700921
- Chuang, P. T., & McMahon, A. P. (1999). Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature, 397(6720), 617-621. https://doi.org/10.1038/17611
- Canettieri, G., Di Marcotullio, L., Greco, A., Coni, S., Antonucci, L., Infante, P., … Gulino, A. (2010). Histone deacetylase and Cullin3- REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nature Cell Biology, 12(2), 132-142. https://doi.org/10.1038/ncb2013
- Amakye, D., Jagani, Z., & Dorsch, M. (2013). Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nature Medicine, 19(11), 1410-1422. https://doi.org/10.1038/nm.3389
- Gajjar, A. J., & Robinson, G. W. (2014). Medulloblastoma -translating discoveries from the bench to the bedside. Nat Rev Clin Oncol, 11(12), 714-722. https://doi.org/10.1038/nrclinonc.2014.181
- Bolden, J. E., Peart, M. J., & Johnstone, R. W. (2006). Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov, 5(9), 769-784. https://doi.org/10.1038/nrd2133
- Goetz, S. C., & Anderson, K. V. (2010). The primary cilium: a signalling centre during vertebrate development. Nature Reviews. Genetics, 11(5), 331-44. https://doi.org/10.1038/nrg2774
- Brun, S. N., Markant, S. L., Esparza, L. A., Garcia, G., Terry, D., Huang, J.- M., … Wechsler-Reya, R. J. (2015). Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma. Oncogene, 34(29), 3770- 3779. https://doi.org/10.1038/onc.2014.304
- Deskin, B., Lasky, J., Zhuang, Y., & Shan, B. (2016). Requirement of HDAC6 for activation of Notch1 by TGF-β1. Scientific Reports, 6, 31086. https://doi.org/10.1038/srep31086
- de Ruijter, A. J. M., van Gennip, A. H., Caron, H. N., Kemp, S., & van Kuilenburg, A. B. P. (2003). Histone deacetylases (HDACs): characterization of the classical HDAC family. The Biochemical Journal, 370(Pt 3), 737-49. https://doi.org/10.1042/BJ20021321
- Batchu, S. N., Brijmohan, A. S., & Advani, A. (2016). The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease. Clinical Science, 130(12), 987-1003. https://doi.org/10.1042/CS20160084
- Ellison, D. (2002). Classifying the medulloblastoma: Insights from morphology and molecular genetics. Neuropathology and Applied Neurobiology. https://doi.org/10.1046/j.1365-2990.2002.00419.x
- Hill, R. E., Heaney, S. J. H., & Lettice, L. A. (2003). Sonic hedgehog: Restricted expression and limb dysmorphologies. Journal of Anatomy. https://doi.org/10.1046/j.1469-7580.2003.00148.x
- Grozinger, C. M., Hassig, C. a, & Schreiber, S. L. (1999). Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proceedings of the National Academy of Sciences of the United States of America, 96(9), 4868-4873. https://doi.org/10.1073/pnas.96.9.4868
- Dai, P., Akimaru, H., Tanaka, Y., Maekawa, T., Nakafuku, M., & Ishii, S. (1999). Sonic hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. Journal of Biological Chemistry, 274(12), 8143- 8152. https://doi.org/10.1074/jbc.274.12.8143
- Gao, L., Cueto, M. A., Asselbergs, F., & Atadja, P. (2002). Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. Journal of Biological Chemistry, 277(28), 25748-25755. https://doi.org/10.1074/jbc.M111871200
- Bhatia, N., Thiyagarajan, S., Elcheva, I., Saleem, M., Dlugosz, A., Mukhtar, H., & Spiegelman, V. S. (2006). Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase. Journal of Biological Chemistry, 281(28), 19320-6. https://doi.org/10.1074/jbc.M513203200
- Atwood, S. X., Chang, A. L. S., & Oro, A. E. (2012). Hedgehog pathway inhibition and the race against tumor evolution. Journal of Cell Biology, 199(2), 193-197. https://doi.org/10.1083/jcb.201207140
- Bischoff, J. R., Anderson, L., Zhu, Y., Mossie, K., Ng, L., Souza, B., … Plowman, G. D. (1998). A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO Journal, 17(11), 3052-3065. https://doi.org/10.1093/emboj/17.11.3052
- Cook, C., Gendron, T. F., Scheffel, K., Carlomagno, Y., Dunmore, J., DeTure, M., & Petrucelli, L. (2012). Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation. Human Molecular Genetics, 21(13), 2936-2945. https://doi.org/10.1093/hmg/dds125
- Bai, R. Y., Staedtke, V., Rudin, C. M., Bunz, F., & Riggins, G. J. (2015). Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis. Neuro-Oncology, 17(4), 545-554. https://doi.org/10.1093/neuonc/nou234
- Dai, P., Shinagawa, T., Nomura, T., Harada, J., Kaul, S. C., Wadhwa, R., … Ishii, S. (2002). Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3. Genes and Development, 16(22), 2843-2848. https://doi.org/10.1101/gad.1017302
- Humke, E. W., Dorn, K. V., Milenkovic, L., Scott, M. P., & Rohatgi, R. 113 (2010). The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins. Genes and Development, 24(7), 670-682. https://doi.org/10.1101/gad.1902910
- Boyault, C., Zhang, Y., Fritah, S., Caron, C., Gilquin, B., So, H. K., … Khochbin, S. (2007). HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes and Development, 21(17), 2172-2181. https://doi.org/10.1101/gad.436407
- Ingham, P. W., & McMahon, A. P. (2001). Hedgehog signaling in animal development: Paradigms and principles. Genes and Development. https://doi.org/10.1101/gad.938601
- Ding, H., Dolan, P. J., & Johnson, G. V. W. (2008). Histone deacetylase 6 interacts with the microtubule-associated protein tau. Journal of Neurochemistry, 106(5), 2119-2130. https://doi.org/10.1111/j.1471- 4159.2008.05564.x
- Eberhart, C. G. (2011). Molecular diagnostics in embryonal brain tumors. In Brain Pathology (Vol. 21, pp. 96-104). https://doi.org/10.1111/j.1750- 3639.2010.00455.x
- Fujii, K., & Miyashita, T. (2014). Gorlin syndrome (nevoid basal cell carcinoma syndrome): Update and literature review. Pediatrics International, 56(5), 667-674. https://doi.org/10.1111/ped.12461
- Berman, D. M., Karhadkar, S. S., Hallahan, A. R., Pritchard, J. I., Eberhart, C. G., Watkins, D. N., … Beachy, P. A. (2002). Medulloblastoma Growth Inhibition by Hedgehog Pathway Blockade. Science, 297(5586), 1559-1561. https://doi.org/10.1126/science.1073733
- de la Roche, M., Ritter, A. T., Angus, K. L., Dinsmore, C., Earnshaw, C. H., Reiter, J. F., & Griffiths, G. M. (2013). Hedgehog signaling controls T cell killing at the immunological synapse. Science, 342(6163), 1247- 1250. https://doi.org/10.1126/science.1244689
- Jacob, L. S., Wu, X., Dodge, M. E., Fan, C.-W., Kulak, O., Chen, B., … Lum, L. (2011). Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling. Science Signaling, 4(157), ra4. https://doi.org/10.1126/scisignal.2001225
- Eggenschwiler, J. T., & Anderson, K. V. (2007). Cilia and developmental signaling. Annual Review of Cell and Developmental Biology, 23, 345- 73. https://doi.org/10.1146/annurev.cellbio.23.090506.123249
- Athar, M., Li, C., Tang, X., Chi, S., Zhang, X., Kim, A. L., … Xie, J. (2004). Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of fas expression and apoptosis. Cancer Research, 64(20), 7545-7552. https://doi.org/10.1158/0008- 5472.CAN-04-1393
- Feldmann, G., Dhara, S., Fendrich, V., Bedja, D., Beaty, R., Mullendore, M., … Maitra, A. (2007). Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: A new paradigm for combination therapy in solid cancers. Cancer Research, 67(5), 2187- 2196. https://doi.org/10.1158/0008-5472.CAN-06-3281
- Geiger, T. R., & Peeper, D. S. (2007). Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis. Cancer Research, 67(13), 6221-6229. https://doi.org/10.1158/0008-5472.CAN-07-0121
- Dhanyamraju, P. K., Holz, P. S., Finkernagel, F., Fendrich, V., & Lauth, M. (2015). Histone deacetylase 6 represents a novel drug target in the oncogenic hedgehog signaling pathway. Molecular Cancer Therapeutics, 14(3), 727-739. https://doi.org/10.1158/1535-
- Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells. Molecular Cancer Therapeutics, 13(12), 2886-97. https://doi.org/10.1158/1535- 7163.MCT-14-0220
- Gupta, S., Takebe, N., & Lorusso, P. (2010). Targeting the Hedgehog pathway in cancer. Therapeutic Advances in Medical Oncology, 2(4), 237-50. https://doi.org/10.1177/1758834010366430
- Frank-Kamenetsky, M., Zhang, X. M., Bottega, S., Guicherit, O., Wichterle, H., Dudek, H., … Porter, J. A. (2002). Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. Journal of Biology, 1(2), 10. https://doi.org/10.1186/1475-4924-1-10
- Delcuve, G. P., Khan, D. H., Davie, J. R., Groth, A., Rocha, W., Verreault, A., … Schnölzer, M. (2012). Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors. Clinical Epigenetics, 4(1), 5. https://doi.org/10.1186/1868-7083-4-5
- Ingram, W. J., Crowther, L. M., Little, E. B., Freeman, R., Harliwong, I., Veleva, D., … Hallahan, A. R. (2013). ABC transporter activity linked to radiation resistance and molecular subtype in pediatric medulloblastoma. Experimental Hematology & Oncology, 2(1), 26. https://doi.org/10.1186/2162-3619-2-26
- de Bont, J. M., Packer, R. J., Michiels, E. M., den Boer, M. L., & Pieters, R. (2008). Biological background of pediatric medulloblastoma and ependymoma: a review from a translational research perspective. Neuro- Oncology, 10(6), 1040-1060. https://doi.org/10.1215/15228517-2008- 059
- Cano, D. a, Murcia, N. S., Pazour, G. J., & Hebrok, M. (2004). Orpk mouse model of polycystic kidney disease reveals essential role of primary cilia in pancreatic tissue organization. Development (Cambridge, England), 131(14), 3457-3467. https://doi.org/10.1242/dev.01189
- Bradley, B. A. (2005). A NIMA-related kinase, Cnk2p, regulates both flagellar length and cell size in Chlamydomonas. Journal of Cell Science, 118(15), 3317-3326. https://doi.org/10.1242/jcs.02455
- Hausmann, G., & Von Mering, C. (2009). The hedgehog signaling pathway: where did it come from. PLoS Biol. Retrieved from http://dx.plos.org/10.1371/journal.pbio.1000146%5Cnpapers2://public ation/uuid/2E1D0CF8-BE44-4A7C-9F59-EC315BC08DF1
- Haycraft, C. J., Banizs, B., Aydin-Son, Y., Zhang, Q., Michaud, E. J., & Yoder, B. K. (2005). Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLOS Genetics, 1(4), e53. https://doi.org/10.1371/journal.pgen.0010053
- Chen, P. B., Hung, J. H., Hickman, T. L., Coles, A. H., Carey, J. F., Weng, Z., … Fazzio, T. G. (2013). Hdac6 regulates Tip60-p400 function in stem cells. eLife, 2013(2), 1-25. https://doi.org/10.7554/eLife.01557
- Gritsko, T. M., Coppola, D., Paciga, J. E., Yang, L., Sun, M., Shelley, S. A., … Cheng, J. Q. (2003). Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clinical Cancer Research, 9(4), 1420-1426.
- Dahmane, N., Lee, J., Robins, P., Heller, P., & Ruiz i Altaba, A. (1997). Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature, 389, 876-881.
- Chen, W. (2004). Activity-Dependent Internalization of Smoothened Mediated by β-Arrestin 2 and GRK2. Science, 306(5705), 2257-2260.
- Altered neural cell fates and medulloblastoma in mouse patched mutants. Science (New York, N.Y.), 277(5329), 1109-13.
- Dorn, K. V., Hughes, C. E., & Rohatgi, R. (2012). A Smoothened-Evc2 Complex Transduces the Hedgehog Signal at Primary Cilia. Developmental Cell, 23(4), 823-835.
- Anand, S., Penrhyn-Lowe, S., & Venkitaraman, A. R. (2003). AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell, 3(1), 51-62.
- Borghesani, P. R., Peyrin, J. M., Klein, R., Rubin, J., Carter, A. R., Schwartz, P. M., … Segal, R. a. (2002). BDNF stimulates migration of cerebellar granule cells. Development (Cambridge, England), 129(6), 1435-1442.
- Izzi, L., Lévesque, M., Morin, S., Laniel, D., Wilkes, B. C., Mille, F., … Charron, F. (2011). Boc and gas1 each form distinct shh receptor complexes with ptch1 and are required for shh-mediated cell proliferation. Developmental Cell, 20(6), 788-801.
- Cancerous stem cells can arise from pediatric brain tumors. Proceedings of the National Academy of Sciences, 100(25), 15178-15183.
- Cooper, A. F., Yu, K. P., Brueckner, M., Brailey, L. L., Johnson, L., McGrath, J. M., & Bale, A. E. (2005). Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development (Cambridge, England), 132, 4407-4417.
- Goepfert, T. M., Adigun, Y. E., Zhong, L., Gay, J., Medina, D., & Brinkley, W. R. (2002). Centrosome amplification and overexpression of aurora A are early events in rat mammary carcinogenesis. Cancer Research, 62(14), 4115-4122.
- Benzing, T., & Walz, G. (2006). Cilium-generated signaling: a cellular GPS? Current Opinion in Nephrology and Hypertension, 15, 245-249.
- Chen, M. H., Wilson, C. W., Li, Y. J., Law, K. K. Lo, Lu, C. S., Gacayan, R., … Chuang, P. T. (2009). Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes and Development, 23(16), 1910-1928.
- Goodrich, L. V., Johnson, R. L., Milenkovic, L., McMahon, J. A., & Scott, M. P. (1996). Conservation of the hedgehog/patched signaling pathway from flies to mice: Induction of a mouse patched gene by Hedgehog. Genes and Development, 10(3), 301-312.
- Haggarty, S. J., Koeller, K. M., Wong, J. C., Grozinger, C. M., & Schreiber, S. L. (2003). Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proceedings of the National Academy of Sciences, 100(8), 4389-4394.
- Drosophila Histone Deacetylase 6 Protects Dopaminergic Neurons against -Synuclein Toxicity by Promoting Inclusion Formation. Molecular Biology of the Cell, 21(13), 2128-2137.
- Apionishev, S., Katanayeva, N. M., Marks, S. a, Kalderon, D., & Tomlinson, A. (2005). Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nature Cell Biology, 7(1), 86-92.
- Han, Y.-G., Kim, H. J., Dlugosz, A. A., Ellison, D. W., Gilbertson, R. J., & Alvarez-Buylla, A. (2009). Dual and opposing roles of primary cilia in medulloblastoma development. Nature Medicine, 15(9), 1062-5.
- Creppe, C., Malinouskaya, L., Volvert, M. L., Gillard, M., Close, P., Malaise, O., … Nguyen, L. (2009). Elongator Controls the Migration and Differentiation of Cortical Neurons through Acetylation of α- Tubulin. Cell, 136(3), 551-564.
- Dierks, C., Grbic, J., Zirlik, K., Beigi, R., Englund, N. P., Guo, G.-R., … Warmuth, M. (2007). Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nature Medicine, 13(8), 944-51.
- Fogarty, M. P., Emmenegger, B. A., Grasfeder, L. L., Oliver, T. G., & Wechsler-Reya, R. J. (2007). Fibroblast growth factor blocks Sonic hedgehog signaling in neuronal precursors and tumor cells. Proceedings of the National Academy of Sciences, 104(8), 2973-2978.
- Adhikary, T., Kaddatz, K., Finkernagel, F., Schönbauer, A., Meissner, W., Scharfe, M., … Müller, R. (2011). Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator- activated receptor-β/δ (PPARβ/δ). PLoS ONE, 6(1).
- Atwood, S. X., Li, M., Lee, A., Tang, J. Y., & Oro, A. E. (2013). GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas. Nature, 494(7438), 484-488.
- De Amezaga, A. O. G., Arregui, O. G., Nuño, S. Z., Sagredo, A. A., & Urizar, J. M. A. (2008). Gorlin-Goltz syndrome: Clinicopathologic aspects. Medicina Oral, Patologia Oral Y Cirugia Bucal.
- Boyault, C., Sadoul, K., Pabion, M., & Khochbin, S. (2007). HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene, 26(37), 5468-76.
- Arsenault, D., Brochu-Gaudreau, K., Charbonneau, M., & Dubois, C. M. (2013). HDAC6 Deacetylase Activity Is Required for Hypoxia-Induced Invadopodia Formation and Cell Invasion. PLoS ONE, 8(2).
- Gradilone, S. A., Radtke, B. N., Bogert, P. S., Huang, B. Q., Gajdos, G. B., & LaRusso, N. F. (2013). HDAC6 inhibition restores ciliary expression and decreases tumor growth. Cancer Research, 73(7), 2259-2270.
- d'Ydewalle, C., Krishnan, J., Chiheb, D. M., Van Damme, P., Irobi, J., Kozikowski, A. P., … Van Den Bosch, L. (2011). HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nature Medicine, 17(8), 968-974.
- Gradilone, S. A., Habringer, S., Masyuk, T. V., Howard, B. N., Masyuk, A. I., & Larusso, N. F. (2014). HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis. American Journal of Pathology, 184(3), 600-608.
- Boyault, C., Gilquin, B., Zhang, Y., Rybin, V., Garman, E., Meyer-Klaucke, W., … Khochbin, S. (2006). HDAC6-p97/VCP controlled polyubiquitin chain turnover. The EMBO Journal, 25(14), 3357-66.
- Espallergues, J., Teegarden, S. L., Veerakumar, A., Boulden, J., Challis, C., Jochems, J., … Berton, O. (2012). HDAC6 Regulates Glucocorticoid Receptor Signaling in Serotonin Pathways with Critical Impact on Stress Resilience. Journal of Neuroscience, 32(13), 4400-4416.
- Brink, G. R. (2007). Hedgehog Signaling in Development and Homeostasis of the Gastrointestinal Tract. Physiol Rev, 87, 1343-1375.
- Huangfu, D., Liu, A., Rakeman, A. S., Murcia, N. S., Niswander, L., & Anderson, K. V. (2003). Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature, 426(6962), 83-87.
- Bijlsma, M. F., Damhofer, H., & Roelink, H. (2012). Hedgehog-Stimulated Chemotaxis Is Mediated by Smoothened Located Outside the Primary Cilium. Science Signaling, 5(August 2012), ra60-ra60.
- Federico, M., & Bagella, L. (2011). Histone deacetylase inhibitors in the treatment of hematological malignancies and solid tumors. J Biomed Biotechnol, 2011(Figure 1), 475641.
- Buonamici, S., Williams, J., Morrissey, M., Wang, A., Guo, R., Vattay, A., … Dorsch, M. (2010). Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma. Science Translational Medicine, 2(51), 51ra70-51ra70.
- Brown, H. G., Kepner, J. L., Perlman, E. J., Friedman, H. S., Strother, D. R., Duffner, P. K., … Burger, P. C. (2000). "Large cell/anaplastic" medulloblastomas: a Pediatric Oncology Group Study. Journal of Neuropathology and Experimental Neurology, 59(10), 857-865.
- Fukada, M., Hanai, A., Nakayama, A., Suzuki, T., Miyata, N., Rodriguiz, R. M., … Kawaguchi, Y. (2012). Loss of deacetylation activity of Hdac6 affects emotional behavior in mice. PLoS ONE, 7(2).
- Akella, J. S., Wloga, D., Kim, J., Starostina, N. G., Lyons-Abbott, S., Morrissette, N. S., … Gaertig, J. (2010). MEC-17 is an alpha-tubulin acetyltransferase. Nature, 467(7312), 218-222.
- Bailey, P., & Cushing, H. (1925). Medulloblastoma Cerebelli: A Common Type of Midcerebellar Glioma of Childhood. Archives of Neurology & Psychiatry, 14(2), 192.
- Berbari, N. F., Sharma, N., Malarkey, E. B., Pieczynski, J. N., Boddu, R., Gaertig, J., … Yoder, B. K. (2013). Microtubule modifications and stability are altered by cilia perturbation and in cystic kidney disease.
- Evgrafov, O. V, Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., … Timmerman, V. (2004). Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nature Genetics, 36(6), 602-606.
- Conacci-Sorrell, M., Ngouenet, C., & Eisenman, R. N. (2010). Myc-nick: A cytoplasmic cleavage product of Myc that promotes ??-tubulin acetylation and cell differentiation. Cell, 142(3), 480-493.
- Hildebrandt, F., Attanasio, M., & Otto, E. (2009). Nephronophthisis: disease mechanisms of a ciliopathy. Journal of the American Society of Nephrology : JASN, 20(1), 23-35.
- Allen, B. L., Song, J. Y., Izzi, L., Althaus, I. W., Kang, J. S., Charron, F., … McMahon, A. P. (2011). Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Developmental Cell, 20(6), 775-787.
- Girdwood, D., Bumpass, D., Vaughan, O. A., Thain, A., Anderson, L. A., Snowden, A. W., … Hay, R. T. (2003). p300 transcriptional repression is mediated by SUMO modification. Molecular Cell, 11(4), 1043-1054.
- Ge, X., Milenkovic, L., Suyama, K., Hartl, T., Purzner, T., Winans, A., … Scott, M. P. (2015). Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma. eLife, 4(September2015).
- Cueva, J. G., Hsin, J., Huang, K. C., & Goodman, M. B. (2012). Posttranslational acetylation of ??-tubulin constrains protofilament number in native microtubules. Current Biology, 22(12), 1066-1074.
- Ho, L., Ali, S. A., Al-Jazrawe, M., Kandel, R., Wunder, J. S., & Alman, B. A. (2013). Primary cilia attenuate hedgehog signalling in neoplastic chondrocytes. Oncogene, 32(47), 5388-96.
- Cervantes, S., Lau, J., Cano, D. a, Borromeo-Austin, C., & Hebrok, M. (2010). Primary cilia regulate Gli/Hedgehog activation in pancreas. Proceedings of the National Academy of Sciences of the United States of America, 107(22), 10109-10114.
- Chen, Y., Gallaher, N., Goodman, R. H., & Smolik, S. M. (1998). Protein clinical outcome. Journal of Clinical Oncology, 29(11), 1424-1430.
- Hatters, D. M. (2008). Protein misfolding inside cells: The case of Huntingtin and Huntington's disease. IUBMB Life.
- Bumcrot, D. A., Takada, R., & McMahon, A. P. (1995). Proteolytic processing yields two secreted forms of sonic hedgehog. Molecular and Cellular Biology, 15(4), 2294-303.
- Hideshima, T., Cottini, F., Ohguchi, H., Jakubikova, J., Gorgun, G., Mimura, N., … Anderson, K. C. (2015). Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma. Blood Cancer Journal, 5(5), e312.
- Coni, S., Mancuso, A. B., Di Magno, L., Sdruscia, G., Manni, S., Serrao, S. M., … Canettieri, G. (2017a). Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma. Scientific Reports, 7, 44079.
- Coni, S., Mancuso, A. B., Di Magno, L., Sdruscia, G., Manni, S., Serrao, S. M., … Canettieri, G. (2017b). Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma. Scientific Reports, 7(February), 44079.
- Forget, A., Bihannic, L., Cigna, S. M., Lefevre, C., Remke, M., Barnat, M., … Ayrault, O. (2014). Shh Signaling Protects Atoh1 from Degradation Mediated by the E3Ubiquitin Ligase Huwe1 in Neural Precursors. Developmental Cell, 29(6), 649-661.
- Huangfu, D., & Anderson, K. V. (2006). Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development (Cambridge, England), 133(1), 3-14.
- Dijkgraaf, G. J. P., Alicke, B., Weinmann, L., Januario, T., West, K., Modrusan, Z., … De Sauvage, F. J. (2011). Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Research, 71(2), 435-444.
- Dahmane, N., & Ruiz i Altaba, a. (1999). Sonic hedgehog regulates the growth and patterning of the cerebellum. Development (Cambridge, England), 126(14), 3089-3100.
- Bishop, B., Aricescu, A. R., Harlos, K., O'Callaghan, C. A., Jones, E. Y., & Siebold, C. (2009). Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. Nature Structural & Molecular Biology, 16(7), 698-703.
- Huang, S. Y., & Yang, J. Y. (2015). Targeting the hedgehog pathway in pediatric medulloblastoma. Cancers.
- Cooper, M. K. (1998). Teratogen-Mediated Inhibition of Target Tissue Response to Shh Signaling. Science, 280(5369), 1603-1607.
- Cooper, G. M., & Hausman, R. E. (2000). The Cell: A Molecular Approach 2nd Edition. Sinauer Associates.
- Endoh-Yamagami, S., Evangelista, M., Wilson, D., Wen, X., Theunissen, J. W., Phamluong, K., … Peterson, A. S. (2009). The Mammalian Cos2
- Haberland, M., Montgomery, R. L., & Olson, E. N. (2009). The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature Reviews. Genetics, 10(1), 32-42.
- Gilbertson, R. J., & Ellison, D. W. (2008). The origins of medulloblastoma subtypes. Annu Rev Pathol, 3, 341-365.
- Aikin, R. A., Ayers, K. L., & Thérond, P. P. (2008). The role of kinases in the Hedgehog signalling pathway. EMBO Reports, 9(4), 330-6.
- Hatton, B. A., Villavicencio, E. H., Tsuchiya, K. D., Pritchard, J. I., Ditzler, S., Pullar, B., … Olson, J. M. (2008). The Smo/Smo model: Hedgehog- induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Research, 68(6), 1768-1776.
- Dahmane, N., Sánchez, P., Gitton, Y., Palma, V., Sun, T., Beyna, M., … Ruiz i Altaba, a. (2001). The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development (Cambridge, England), 128(24), 5201-5212.
- Bosanac, I., Maun, H. R., Scales, S. J., Wen, X., Lingel, A., Bazan, J. F., … Lazarus, R. a. (2009). The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling. Nature Structural & Molecular Biology, 16(7), 691-697.
- Incardona, J. P., Gaffield, W., Kapur, R. P., & Roelink, H. (1998). The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development (Cambridge, England), 125(18), 3553-3562.
- Batchu, S. N., Brijmohan, A. S., Advani, A., Olsen, J. V., Blagoev, B., Gnad, F., … Guggino, W. B. (2016). The therapeutic hope for HDAC6
- Dehmel, F., Weinbrenner, S., Julius, H., Ciossek, T., Maier, T., Stengel, T., … Beckers, T. (2008). Trithiocarbonates as a novel class of HDAC inhibitors: SAR studies, isoenzyme selectivity, and pharmacolozgical profiles. Journal of Medicinal Chemistry, 51(13), 3985-4001.
- Aldana-Masangkay, G. I., Rodriguez-Gonzalez, A., Lin, T., Ikeda, A. K., Hsieh, Y.-T., Kim, Y.-M., … Sakamoto, K. M. (2011). Tubacin suppresses proliferation and induces apoptosis of acute lymphoblastic leukemia cells. Leukemia & Lymphoma, 52(8), 1544-55.
- Dean, M., Fojo, T., & Bates, S. (2005). Tumour stem cells and drug resistance. Nature Reviews Cancer, 5(4), 275-284.
- Bazzaro, M., Lin, Z., Santillan, A., Lee, M. K., Wang, M. C., Chan, K. C., … Roden, R. B. S. (2008). Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor. Clinical Cancer Research, 14(22), 7340-7347.
- Aszterbaum, M., Beech, J., & Epstein Jr., E. H. (1999). Ultraviolet radiation mutagenesis of hedgehog pathway genes in basal cell carcinomas. J Investig Dermatol Symp Proc, 4(1), 41-45.
- Corbit, K. C., Aanstad, P., Singla, V., Norman, A. R., Stainier, D. Y. R., & Reiter, J. F. (2005). Vertebrate Smoothened functions at the primary cilium. Nature, 437(October), 1018-1021.
- Day, E. S., Wen, D., Garber, E. a, Hong, J., Avedissian, L. S., Rayhorn, P., … Baker, D. P. (1999). Zinc-dependent structural stability of human Sonic hedgehog. Biochemistry, 38(45), 14868-14880.