SOX2OT Long Noncoding RNA Is Regulated by the UPR in Oestrogen Receptor-Positive Breast Cancer

Carole Ferraro-Peyret,Marjan E Askarian-Amiri,Herah Hansji,Euphemia Y Leung,Debina Sarkar,Bruce C Baguley,Wayne R Joseph

doi:10.3390/sci3020026

Abstract

Endoplasmic reticulum (ENR) stress perturbs cell homeostasis and induces the unfolded protein response (UPR). In breast cancer, this process is activated by oestrogen deprivation and is associated with tamoxifen resistance. We present evidence that the transcription factor SOX2 and the long noncoding RNA SOX2 overlapping transcript (SOX2OT) are upregulated in oestrogen receptor-positive (ER+) breast cancer and in response to oestrogen deprivation. We examined the effect of the UPR on SOX2 and SOX2OT expression and the effect of SOX2OT on UPR pathways in breast cancer cell lines. The induction of the UPR by thapsigargin or glucose deprivation upregulates SOX2OT expression. This upregulation is also shown with the anti-oestrogen 4OH-tamoxifen and mTOR inhibitor everolimus in ER + breast cancer cells that are sensitive to oestrogen deprivation or everolimus treatment. SOX2OT overexpression decreased BiP and PERK expression. This effect of SOX2OT overexpression was confirmed on BiP and PERK pathway by q-PCR. Our results show that a long noncoding RNA regulates the UPR and evince a new function of SOX2OT as a participant of ENR stress reprogramming of breast cancer cells.

Highlights

Despite extensive studies in breast cancer and more detailed knowledge of its molecular pathways, many aspects of breast cancer cell regulation are still enigmatic
SOX2 overlapping transcript (SOX2OT) and SOX2 transcripts are upregulated in tamoxifen-resistant cell lines [4,32]
Our results show that the expression of BiP and PERK decreased in SOX2OT

Summary

Introduction

Despite extensive studies in breast cancer and more detailed knowledge of its molecular pathways, many aspects of breast cancer cell regulation are still enigmatic. The dysregulation of several lncRNAs in breast cancer has been reported [1,2,3] and the functions of this class of transcript require elucidation. Within an intronic region of the gene specifying the SOX2 overlapping transcript (SOX2OT) lncRNA lies the SOX2 gene, one of the main regulators of pluripotency (Figure 1, [4]). As described previously [4], SOX2 and SOX2OT are differentially expressed in ER+ and ER- breast cancer. They are both upregulated in suspension culture under conditions that prioritise spheroid formation. We suggest that in breast cancer, SOX2OT is key to the regulation of SOX2 expression. The mechanism of action of SOX2OT in breast cancer remains to be

Methods

Results

Conclusion