Trim32 facilitates degradation of MYCN on spindle poles and induces asymmetric cell division in human neuroblastoma cells

Cancer Res. 2014 Oct 1;74(19):5620-30. doi: 10.1158/0008-5472.CAN-14-0169. Epub 2014 Aug 6.

Abstract

Asymmetric cell division (ACD) is a physiologic process during development and tissue homeostasis. ACD produces two unequal daughter cells: one has stem/progenitor cell activity and the other has potential for differentiation. Recent studies showed that misregulation of the balance between self-renewal and differentiation by ACD may lead to tumorigenesis in Drosophila neuroblasts. However, it is still largely unknown whether human cancer stem-like cells exhibit ACD or not. Here, using human neuroblastoma cells as an ACD model, we found that MYCN accumulates at spindle poles by GSK-3β phosphorylation during mitosis. In parallel, the ACD-related ubiquitin ligase Trim32 was recruited to spindle poles by CDK1/cyclin B-mediated phosphorylation. Trim32 interacted with MYCN at spindle poles during mitosis, facilitating proteasomal degradation of MYCN at spindle poles and inducing ACD. Trim32 also suppressed sphere formation of neuroblastoma-initiating cells, suggesting that the mechanisms of ACD produce differentiated neuroblastoma cells that will eventually die. Thus, Trim32 is a positive regulator of ACD that acts against MYCN and should be considered as a tumor-suppressor candidate. Our findings offer novel insights into the mechanisms of ACD and clarify its contributions to human tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / physiology*
  • Cell Line, Tumor
  • Fluorescent Antibody Technique, Indirect
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Mitosis
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / metabolism*
  • Phosphorylation
  • Proteolysis
  • Signal Transduction
  • Spindle Poles / metabolism*
  • Substrate Specificity
  • Transcription Factors / physiology*
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases

Substances

  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Transcription Factors
  • Tripartite Motif Proteins
  • TRIM32 protein, human
  • Ubiquitin-Protein Ligases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3