Pardeshi, Jyotsna
(2022)
The role of human DEAD-box protein
DDX3X in the activation and function
of Estrogen Receptor-alpha.
PhD thesis, National University of Ireland Maynooth.
Abstract
The human DEAD-box RNA helicase DDX3X was shown to be involved in innate immune signalling
pathways mediated by IKKε and TBK1. Interestingly, both DDX3 and IKKɛ have independently been
shown to act as breast cancer oncogenes. In breast cancer, DDX3 expression was shown to be
upregulated and linked with tumourigenesis. IKKɛ was suggested to phosphorylate Estrogen
receptor alpha (ERα) at Serine-167 and drive expression of ERα-responsive genes in an estrogen-
independent manner, leading to cell proliferation and resistance to anti-estrogen treatment. The
current study aimed to investigate whether DDX3 and IKKɛ also collaborate in the activation of ERα.
This work suggests that DDX3 and IKKɛ collaborate to mediate ERα phosphorylation and activation,
akin to the mechanism that the MU Host-Pathogen Lab elucidated for IRF3 activation in innate
immune signalling. DDX3 knockdown in breast cancer cell lines resulted in reduced ERα
phosphorylation, reduced ERE-controlled reporter gene expression, decreased expression
of ERα target genes, decreased cell proliferation. Vice versa, overexpression of DDX3 resulted in
enhanced ERα phosphorylation and activity. This study provides evidence from co-
immunoprecipitation and pulldown experiments that, DDX3 directly binds to ERα to regulate its
activation and function. Present work further analyses the effect of DDX3 knockdown on the
proteome of the T47D breast cancer cell line grown under estrogen-replete and -deplete conditions.
DDX3 knockdown lead to decreased expression of three chaperones involved in regulating ERα
activity, Hsp90, Hsp70 and FKBP52. DDX3 was previously also shown to activate β-catenin by
regulating CK1ε in Wnt pathway activation, and β-catenin was linked to an increased ERα protein
level. This work demonstrates that, CK1ε and β-catenin might also be contributing to activation of
ERα. In conclusion, this work provides evidence for a novel molecular role of DDX3 in activation of
ERα, highlighting the oncogenic effect of DDX3 in breast cancer and linking it to endocrine therapy
resistance.
| Item Type: |
Thesis
(PhD)
|
| Keywords: |
human DEAD-box protein DDX3X; activation; function;
Estrogen Receptor-alpha; |
| Academic Unit: |
Faculty of Science and Engineering > Biology |
| Item ID: |
15840 |
| Depositing User: |
IR eTheses
|
| Date Deposited: |
13 Apr 2022 14:03 |
| URI: |
|
| Use Licence: |
This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available
here |
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