Inhibition of RNA Binding in SND1 Increases the Levels of miR-1-3p and Sensitizes Cancer Cells to Navitoclax

Saara Lehmusvaara; Teemu Haikarainen; Juha Saarikettu; Guillermo Martinez Nieto; Olli Silvennoinen

doi:10.3390/cancers14133100

Inhibition of RNA Binding in SND1 Increases the Levels of miR-1-3p and Sensitizes Cancer Cells to Navitoclax

Cancers (Basel). 2022 Jun 24;14(13):3100. doi: 10.3390/cancers14133100.

Authors

Saara Lehmusvaara^{1

2}, Teemu Haikarainen^{1

2}, Juha Saarikettu³, Guillermo Martinez Nieto^{1

2}, Olli Silvennoinen^{1

2

3

4}

Affiliations

¹ Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.
² Tays Cancer Center, Tampere University Hospital, 33520 Tampere, Finland.
³ HiLIFE, Helsinki Institute of Life Science, University of Helsinki, 00790 Helsinki, Finland.
⁴ Fimlab Laboratories, Pirkanmaa Hospital District, 33520 Tampere, Finland.

Abstract

SND1 is an RNA-binding protein overexpressed in large variety of cancers. SND1 has been proposed to enhance stress tolerance in cancer cells, but the molecular mechanisms are still poorly understood. We analyzed the expression of 372 miRNAs in the colon carcinoma cell line and show that SND1 silencing increases the expression levels of several tumor suppressor miRNAs. Furthermore, SND1 knockdown showed synergetic effects with cancer drugs through MEK-ERK and Bcl-2 family-related apoptotic pathways. To explore whether the SND1-mediated RNA binding/degradation is responsible for the observed effect, we developed a screening assay to identify small molecules that inhibit the RNA-binding function of SND1. The screen identified P2X purinoreceptor antagonists as the most potent inhibitors. Validation confirmed that the best hit, suramin, inhibits the RNA binding ability of SND1. The binding characteristics and mode of suramin to SND1 were characterized biophysically and by molecular docking that identified positively charged binding cavities in Staphylococcus nuclease domains. Importantly, suramin-mediated inhibition of RNA binding increased the expression of miR-1-3p, and enhanced sensitivity of cancer cells to Bcl-2 inhibitor navitoclax treatment. Taken together, we demonstrate as proof-of-concept a mechanism and an inhibitor compound for SND1 regulation of the survival of cancer cells through tumor suppressor miRNAs.

Keywords: RNA binding protein; colon cancer; inhibitor screen; stress response.

Grants and funding

This research was funded by the Academy of Finland (grant number 335437), Sigrid Jusélius Foundation (grant number 1152), Finnish Cancer Foundation (grant number 4708167), Jane and Aatos Erkko Foundation, Tampere Tuberculosis Foundation (grant number 2019), and Pirkanmaa hospital district competitive research funding.