Inhibition of ID1–BMPR2 intrinsic signaling sensitizes glioma stem cells to differentiation therapy

Xiong Jin, Xun Jin, Leo J.Y. Kim, Deobrat Dixit, Hee Young Jeon, Eun Jung Kim, Jun Kyum Kim, Seon Yong Lee, Jinlong Yin, Jeremy N. Rich, Hyunggee Kim

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear. Experimental Design: We performed in silico screening and in vitro validation studies through Western blotting, qRT-PCR for treatment of WNT and SHH signaling inhibitors, and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice. Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through miRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacologic blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice. Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation.

Original languageEnglish
Pages (from-to)383-394
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number2
DOIs
Publication statusPublished - 2018 Jan 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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