NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth

Panneerselvam Jayabal, Fuchun Zhou, Xiufen Lei, Xiuye Ma, Barron Blackman, Susan E Weintraub, Peter J. Houghton, Yuzuru Shiio

Research output: Contribution to journalArticlepeer-review

Abstract

BAF chromatin remodeling complexes play important roles in chromatin regulation and cancer. Here, we report that Ewing sarcoma cells are dependent on the autocrine signaling mediated by NELL2, a secreted glycoprotein that has been characterized as an axon guidance molecule. NELL2 uses Robo3 as the receptor to transmit critical growth signaling. NELL2 signaling inhibits cdc42 and upregulates BAF complexes and EWS-FLI1 transcriptional output. We demonstrate that cdc42 is a negative regulator of BAF complexes, inducing actin polymerization and complex disassembly. Furthermore, we identify NELL2highCD133highEWS-FLI1high and NELL2lowCD133lowEWS-FLI1low populations in Ewing sarcoma, which display phenotypes consistent with high and low NELL2 signaling, respectively. We show that NELL2, CD133, and EWS-FLI1 positively regulate each other and upregulate BAF complexes and cell proliferation in Ewing sarcoma. These results reveal a signaling pathway regulating critical chromatin remodeling complexes and cancer cell proliferation.

Original languageEnglish (US)
Article number109254
JournalCell Reports
Volume36
Issue number1
DOIs
StatePublished - Jul 6 2021

Keywords

  • BAF complex
  • CD133
  • cdc42
  • Ewing sarcoma
  • NELL2
  • Robo3
  • secretome proteomics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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