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dc.contributor.advisor Yao, Tso-Pang en_US
dc.contributor.author Lee, Yishan en_US
dc.date.accessioned 2008-08-01T12:53:15Z
dc.date.available 2008-08-01T12:53:15Z
dc.date.issued 2008-04-21 en_US
dc.identifier.uri http://hdl.handle.net/10161/654
dc.description Dissertation en_US
dc.description.abstract <p>Reversible acetylation has emerged as an important post-translational modification that rivals phosphorylation in regulating chromatin structure and gene expression. Acetylation of histone is associated with transcriptional activation while deacetylation is linked to transcriptional repression. Moreover, histone deacetylase inhibitors induce growth arrest, differentiation and apoptosis of cancer cells and therefore appear to be promising anti-tumor agents. While transcriptional deregulation is thought to be the main mechanism underlying their therapeutic effects, the exact mechanisms and targets by which HDAC inhibitors, which are mostly non-specific, achieve their anti-tumor effects remain poorly understood. In other words, it is not known which and how each HDAC members are involved in supporting tumor growth.</p><p>In this thesis, I have showed that HDAC6, a cytoplasmic localized and cytoskeleton-associated deacetylase, is required for efficient oncogenic transformation and tumor formation. I have found that HDAC6 expression is induced upon oncogenic Ras-induced transformation in both human somatic cells and murine fibroblasts. Conversely, murine fibroblasts deficient in HDAC6 are more resistant to both oncogenic Ras and ErbB2-dependent transformation, indicating a critical role for HDAC6 in oncogene-induced transformation. Supporting this hypothesis, inactivation of HDAC6 in several human cancer cell lines effectively impairs anchorage-independent growth <em>in vitro</em> and their ability to form tumors in immunocompromised mice. I have demonstrated that the impairment of anchorage independent growth in HDAC6 deficient cells is associated with increased anoikis and mechanistically a defect in activation of the AKT and ERK kinase cascades. Additionally, <em>HDAC6 </em>null mice are more resistant to two-stage chemical carcinogen-induced skin tumors. Finally, I have demonstrated that the tumor-promoting effect of HDAC6 is probably mediated through the molecular chaperon Hsp90. While Hsp90 is known to be deacetylated by HDAC6 and has been implicated in stabilizing Raf-1 and ErbB2, I have found that suppression of HDAC6 impairs the stability of Raf-1 and the association between Hsp90 and ErbB2.</p><p>In conclusion, my work provides the first experimental evidence that of all the HDAC members, the cytoplasmic deacetylase HDAC6 is required for efficient oncogenic transformation, indicating that reversible acetylation plays a critical role in regulating cellular functions of non-histone non-nuclear cytoplasmic proteins that contributes to malignant transformation. Furthermore, this work identifies HDAC6 as an important component underlying the anti-tumor effects of HDAC inhibitors.</p> en_US
dc.format.extent 4569563 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Biology, Molecular en_US
dc.subject Biology, Physiology en_US
dc.subject Biology, Cell en_US
dc.subject HDAC en_US
dc.subject deacetylation en_US
dc.subject transformation en_US
dc.subject anoikis en_US
dc.title Roles of Cytoplasmic Deacetylase Hdac6 in Oncogenic Tumorigenesis en_US
dc.type Dissertation en_US
dc.department Molecular Cancer Biology en_US
duke.embargo.months 12 en_US
dc.date.accessible 2009-08-02T05:00:04Z

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