Cell Reports: NELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growthNELL2-cdc42 signaling regulates BAF complexes and Ewing sarcoma cell growth (Shiio, Houghton)

Cell Reports

Panneerselvam Jayabal1, Fuchun Zhou1, Xiufen Lei1, XiuyeMa1, Barron Blackman1, Susan T.Weintraub23, Peter J.Houghton134, YuzuruShiio1235

Highlights

The autocrine signaling mediated by NELL2 maintains Ewing sarcoma cell growth
NELL2 signaling inhibits cdc42 and enhances EWS-FLI1 transcriptional output
NELL2-cdc42 signaling regulates the assembly and the stability of BAF complexes
Ewing sarcoma harbors cell populations displaying high and low NELL2 signaling

Summary

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.

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Article Categories: Research Paper