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Ncoa3 coactivator is a transcriptional target of xbp1 and regulates perk–eif2α–atf4 signalling in breast cancer

Gupta, A
; 
Hossain, M M
; 
Miller, N
; 
Kerin, M
; 
Callagy, G
; 
Gupta, S
Repository DOI
Publication Date
2016-04-25
Keywords
unfolded protein response, steroid-receptor coactivator-3, endoplasmic-reticulum stress, cell fate decisions, er stress, translational regulation, messenger-rna, perk, activation, expression
Type
Article
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Citation
Gupta, A; Hossain, M M; Miller, N; Kerin, M; Callagy, G; Gupta, S (2016). Ncoa3 coactivator is a transcriptional target of xbp1 and regulates perk–eif2α–atf4 signalling in breast cancer. Oncogene 35 (45), 5860-5871
Abstract
XBP1 is a multitasking transcription factor and a key component of the unfolded protein response (UPR). Despite the wealth of knowledge about the role of XBP1 in luminal/ER-positive breast cancer, not much is known about the effectors of XBP1 in this context. Here we show that NCOA3 is a transcriptional target of XBP1. We observed increased expression of NCOA3 during conditions of UPR and oestrogen (E2) stimulation. Further investigations revealed a role for the IRE1-XBP1 axis in the induction of NCOA3 during UPR and oestrogen signalling. We identify a novel role for NCOA3 in activation of PERK-ATF4 axis during UPR where knockdown of NCOA3 compromised the optimal activation of the PERK-ATF4 pathway. We found that NCOA3 is required for induction of XBP1 during E2 stimulation and uncover a positive feedback regulatory loop that maintains high levels of NCOA3 and XBP1 in breast cancer. Furthermore, upregulated NCOA3 was required for XBP1-mediated resistance to antihormonal agents. Increased expression of NCOA3 was associated with poor prognosis and higher levels of XBP1-S in breast cancer tissues. Our results uncover a novel steroid hormone-independent role for NCOA3 in UPR signalling. Further we identify a positive feedback regulatory loop consisting of XBP1 and NCOA3 that maintains high levels of NCOA3 and XBP1 expression in breast cancer tissues. Taken together our data identify XBP1-NCOA3 axis that regulates cell fate decisions in ER-positive breast cancer cells.
Funder
Publisher
Springer Nature
Publisher DOI
10.1038/onc.2016.121
Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland
cbn
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Externally hosted open access publications with University of Galway authors (2)