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YBX1/lncRNA SBF2-AS1 interaction regulates proliferation and tamoxifen sensitivity via PI3K/AKT/MTOR signaling in breast cancer cells

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Abstract

Background

Y-box binding protein 1 (YBX1) is a multifunctional oncoprotein that can interact with several long non-coding RNAs (lncRNAs) to regulate metastasis in malignancies including breast cancer (BC). In the present study, we demonstrated the association of YBX1 with oncogenic lncRNA SBF2-AS1 (SET-binding factor 2 antisense RNA 1) via PI3K/AKT/mTOR signaling to regulate BC cell proliferation. We further explored the involvement of the YBX1/SBF2-AS1/PI3K/AKT/mTOR axis in the restoration of tamoxifen (TAM) sensitivity.

Methods and results

YBX1-SBF2-AS1 association was predicted in silico and verified by RNA immunoprecipitation (RIP)-qPCR assay. Transfection experiments, Real-time RT PCR, Western blots, Phospho AKT/mTOR antibody array kit, and cell proliferation/apoptosis assays were employed to detect the YBX1/SBF2-AS1/ PI3K/AKT/mTOR axis and its effects upon TAM treatment in vitro. We identified that the YBX1 protein specifically binds to lncRNA SBF2-AS1. Our transfection experiments in MCF-7 and MDA-MB-468 cells with SBF2-AS1 silenced or overexpressed YBX1 plasmids, and their negative controls revealed that YBX1 regulates the expression of SBF2-AS1 by forming a positive feedback loop for its activation. We further demonstrated YBX1-SBF2-AS1 association exerts its effects on cell proliferation via PI3K/AKT/mTOR signaling pathway. Furthermore, we observed an increase in TAM sensitivity in BC cells after the knockdown of YBX1-SBF2-AS1 marked by decreased cell proliferation through disruption of the PI3K/AKT/mTOR axis.

Conclusion

Our study has identified a novel YBX1/SBF2-AS1/PI3K/AKT/mTOR regulatory axis which may serve as a potential target to improve the effectiveness and efficacy of TAM treatment in BC.

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Data availability

Data will be made available on reasonable request.

Abbreviations

BC:

Breast cancer

YBX1:

Y-box binding protein

LncRNAs:

Long non-coding RNAs

TAM:

Tamoxifen

ceRNA:

Competitive endogenous RNA

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Acknowledgements

We extend our gratitude to the Central University of Kerala for their core grant support. We thank the reviewers for their critical insights to improve the manuscript.

Funding

TV acknowledges grants from DST-SERB (YSS/2014/000061) and DBT (BT/PR23887/MED/30/1871/2017). SAH acknowledges CSIR for fellowship.

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  1. Department of Biochemistry and Molecular Biology, Central University of Kerala, Kasaragod, Kerala, 671316, India

    Shaharbhanu A. Hussain & Thejaswini Venkatesh

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  1. Shaharbhanu A. Hussain
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SAH and TV conceived the project and designed the experiments. SAH performed all the experiments and data analysis. SAH wrote the first draft of the manuscript. TV edited the draft of the manuscript. SAH and TV revised the manuscript. TV provided reagents/materials and supervised the project.

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Correspondence to Thejaswini Venkatesh.

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Hussain, S.A., Venkatesh, T. YBX1/lncRNA SBF2-AS1 interaction regulates proliferation and tamoxifen sensitivity via PI3K/AKT/MTOR signaling in breast cancer cells. Mol Biol Rep 50, 3413–3428 (2023). https://doi.org/10.1007/s11033-023-08308-5

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