Histone deacetylase 6 represents a novel drug target in the oncogenic Hedgehog signaling pathway

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)...

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1. Verfasser: Dhanyamraju, Pavan Kumar
Beteiligte: Lauth, Matthias (PD Dr,) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Englisch
Veröffentlicht: Philipps-Universität Marburg 2017
Molekularbiologie und Tumorforschung
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Zusammenfassung: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.
Beschreibung:165 pages.
DOI:https://doi.org/10.17192/z2017.0629