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

Research output: Contribution to journalArticleScientificpeer-review

4 Citations (Scopus)
26 Downloads (Pure)

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 bind-ing/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.

Original languageEnglish
Article number3100
Number of pages17
JournalCancers
Volume14
Issue number13
DOIs
Publication statusPublished - Jun 2022
Publication typeA1 Journal article-refereed

Keywords

  • colon cancer
  • inhibitor screen
  • RNA binding protein
  • stress response

Publication forum classification

  • Publication forum level 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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