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NCOA3 coactivator is a transcriptional target of XBP1 and regulates PERK-eIF2α-ATF4 signalling in breast cancer.

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.

SUBMITTER: Gupta A

PROVIDER: S-EPMC4979996 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR) mediated via the activation of three transmembrane proteins IRE1, PERK and ATF6. Signalling through these proteins is aimed at enhancing the ER folding capacity and reducing the folding load. If these processes fail to re-establish protein homeostasis within the ER, then cell death prevails via apoptosis. How the shift from pro-survival to pro-apoptotic signalling is regulated remains unclear with both IRE1 and PERK signalling associated with pro-survival as well as pro-apoptotic signalling. To investigate the temporal activation of IRE1 and PERK in live cells and their relationship to cellular fate, we devised single cell reporters for both ER stress signalling branches. SH-SY5Y neural cells stably expressing these fluorescent protein reporter constructs to monitor IRE1-splicing activity and PERK-mediated ATF4-translation were imaged using single cell and high content time lapse live cell microscopy. We could correlate an early onset and attenuation of XBP1 splicing in the IRE1-reporter cells as cytoprotective. Indeed, silencing of IRE1 expression using shRNA inhibited splicing of XBP1 resulting in an early onset of cell death. In contrast, in the PERK-reporter cells, we observed that a slow rate of ATF4-translation and late re-initiation of general translation coincided with cells which were resistant to ER stress-induced cell death. Interestingly, whereas silencing of PERK did not affect overall levels of cell death in response to ER stress, it did increase sensitivity to ER stressors at early time points following treatment. Our results suggest that apoptosis activation in response to ER stress is not caused by a preferential activation of a single UPR branch, or by a switch from one branch to the other. Rather, our data indicated that the relative timing of IRE1 and PERK signalling determines the shift from cell survival to apoptosis.

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NCOA3 coactivator is a transcriptional target of XBP1 and regulates PERK-eIF2α-ATF4 signalling in breast cancer.

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