NCOA3 coactivator is a transcriptional target of XBP1 and regulates PERK-eIF2α-ATF4 signalling in breast cancer.
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.
Discipline of Pathology, School of Medicine, Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland.
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Gupta
Discipline of Pathology, School of Medicine, Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland.
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Hossain
Discipline of Surgery, School of Medicine, Clinical Science Institute, National University of Ireland, Galway, Ireland.
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Miller
Discipline of Surgery, School of Medicine, Clinical Science Institute, National University of Ireland, Galway, Ireland.
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Kerin
Discipline of Pathology, School of Medicine, Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland.
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Callagy
Discipline of Pathology, School of Medicine, Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland.
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Gupta
D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1 / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D000071717:X-Box Binding Protein 1; D051701:Activating Transcription Factor 4; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases