The epidermal growth factor receptor (EGFR) plays a critical role in both normal development and human cancer. Studies of EGFR and its binding partners continue to reveal additional dynamic patterns of pathway activation, and further layers of EGFR regulation through intracellular signaling, including those that may lead to cancer. Now, a Spanish National Cancer Research Centre-led team of researchers have identified a new EGFR-binding protein that leads to pathway deregulation and glioblastoma.
According to the team’s published paper in Nature, LC-MS/MS analyses of human cancer cell line extracts revealed proteins that were immunoprecipitated along with EGFR. Within this group, a notable RNA-binding protein RanBP6 was identified. This protein had not yet been reported or functionally characterized and thus became the subject of the team’s investigation.
The authors show that RanBP6 is an importin family member that regulates STAT3, a key transcription factor that represses transcription of EGFR. Silencing of RanBP6 impairs translocation of STAT3 into the nucleus. This results in transcriptional derepression of EGFR, and subsequently an increased EGFR pathway output.
Specifically for the glioma cancer type, focal deletions of the RanBP6 locus have been found in a subset of glioblastoma patients. Silencing of RanBP6 also promoted glioma growth in a mouse model by upregulating EGFR expression. Finally, xenografting human glioma cell lines into mice with reconstituted RanBP6 has led to a reduction in tumor growth.
"Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway. We have identified a new link between the Ran-GTPase nuclear transport pathway and key cancer signaling pathways which warrant further study as inhibitors targeting nuclear transporters enter clinical evaluation as cancer therapeutics,” said study first author Barbara Oldrini.
Image: Model of EGFR regulation by RanBP6. This mechanism of EGFR regulation serves to repress EGFR transcription at steady state. Cancer cells inactivate this physiologic mechanism of EGFR regulation through deletion of the RANBP6 gene. Image courtesy of Massimo Squatrito, Ingo K. Mellinghoff and Nature.