We use cookies to ensure that we give you the best experience on our website. By continuing to browse this repository, you give consent for essential cookies to be used. You can read more about our Privacy and Cookie Policy.

Durham e-Theses
You are in:

Interplay between Histone Deacetylases in the Modulation of Matrix Metalloproteinase-10 (MMP-10) Expression in Lung Cancer

YOUNG, NATALIE (2017) Interplay between Histone Deacetylases in the Modulation of Matrix Metalloproteinase-10 (MMP-10) Expression in Lung Cancer. Doctoral thesis, Durham University.

PDF - Accepted Version


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
Thesis Date:2017
Copyright:Copyright of this thesis is held by the author
Deposited On:04 Dec 2017 12:12

Social bookmarking: del.icio.usConnoteaBibSonomyCiteULikeFacebookTwitter