YOUNG, NATALIE (2017) Interplay between Histone Deacetylases in the Modulation of Matrix Metalloproteinase-10 (MMP-10) Expression in Lung Cancer. Doctoral thesis, Durham University.
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Matrix Metalloproteinase-10 (MMP-10) has been shown to be overexpressed in human non-small cell lung cancer (NSCLC), wherein it is proteolytically active, se-creted predominantly by tumour cells, and implicated in retarding angiogenesis through repression of tumour vasculature development. Previous studies have indi-cated a role for the histone deacetylase (HDAC) enzymes, specifically HDAC7, in the regulation of MMP-10, with elevated levels of HDAC7 repressing MMP-10 expres-sion and promoting successful blood vessel formation. The aim of this project was to evaluate the relationship between MMP-10 and HDACs and whether perturba-tion of the HDAC7/MMP-10 pathway maybe a viable opportunity for therapeutic exploitation in NSCLC. Using an in vitro model of NSCLC a central role for histone deacetylases (HDACs) in regulation of MMP-10 expression was confirmed. Although inhibition of HDAC activity increased MMP-10 expression and activity, selective in-hibition of the class-II HDAC7 had no effect. However, siRNA-mediated repression of HDAC7 expression caused a significant elevation in MMP-10 expression and ac-tivity, supporting a central role for the presence but not enzymatic activity of HDAC7 in the control of MMP-10 levels within NSCLC. Despite the lack of a role for HDAC7 enzyme activity in control of MMP-10, the initial observation that pan-inhibition of HDAC activity repressed MMP-10 expression implicated a wider in-volvement for HDACs in regulation of MMP-10. Consequently, this study using both siRNA and pharmacological inhibitors confirmed an additional role for the presence and enzymatic activity of the class-I subfamily member HDAC3 in the regulation of MMP-10 in NSCLC. These data indicated an interplay between the class-I HDAC3 and class-II HDAC7 in the regulation of MMP-10 expression and activity, a relation-ship supported by the previously suggested role for HDAC7 in the nuclear shuttling and subsequent enzymatic functionality of HDAC3. This study thereby identifies and offers a novel molecular mechanism for HDAC-mediated control of MMP-10 in NSCLC. Further work is required to exploit this relationship toward improved treat-ment of NSCLC in the clinic.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Keywords:||Matrix Metalloproteinase, Histone Deacetylase, NSCLC|
|Faculty and Department:||Faculty of Social Sciences and Health > Medicine and Health, School of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||04 Dec 2017 12:12|