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Title: Interplay between histone deacetylases in the modulation of matrix metalloproteinase-10 (MMP-10) expression in lung cancer
Author: Young, Natalie
ISNI:       0000 0004 6497 287X
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2017
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available