RUNX1-Survivin Axis Is a Novel Therapeutic Target for Malignant Rhabdoid Tumors

Mol Cells. 2022 Dec 31;45(12):886-895. doi: 10.14348/molcells.2022.2031. Epub 2022 Dec 12.

Abstract

Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric malignancy with no effective therapy. Therefore, it is necessary to identify a target for the development of novel molecule-targeting therapeutic agents. In this study, we report the importance of the runt-related transcription factor 1 (RUNX1) and RUNX1-Baculoviral IAP (inhibitor of apoptosis) Repeat-Containing 5 (BIRC5/survivin) axis in the proliferation of MRT cells, as it can be used as an ideal target for anti-tumor strategies. The mechanism of this reaction can be explained by the interaction of RUNX1 with the RUNX1-binding DNA sequence located in the survivin promoter and its positive regulation. Specific knockdown of RUNX1 led to decreased expression of survivin, which subsequently suppressed the proliferation of MRT cells in vitro and in vivo. We also found that our novel RUNX inhibitor, Chb-M, which switches off RUNX1 using alkylating agent-conjugated pyrrole-imidazole polyamides designed to specifically bind to consensus RUNX-binding sequences (5'-TGTGGT-3'), inhibited survivin expression in vivo. Taken together, we identified a novel interaction between RUNX1 and survivin in MRT. Therefore the negative regulation of RUNX1 activity may be a novel strategy for MRT treatment.

Keywords: RUNX1; malignant rhabdoid tumor; polyamide; survivin.

MeSH terms

  • Apoptosis
  • Base Sequence
  • Cell Line, Tumor
  • Core Binding Factor Alpha 2 Subunit* / genetics
  • Humans
  • Rhabdoid Tumor* / drug therapy
  • Rhabdoid Tumor* / genetics
  • Survivin*

Substances

  • Core Binding Factor Alpha 2 Subunit
  • RUNX1 protein, human
  • Survivin
  • BIRC5 protein, human