HSP90-CDC37 Functions as a Chaperone for the Oncogenic FGFR3-TACC3 Fusion

Authors

Tao Li
Farideh Mehraein-Ghomi
M Elizabeth Forbes
Sanjeev V Namjoshi
E Ashley Ballard
Qianqian Song
Ping-Chieh Chou
Xuya Wang
Brittany C Parker Kerrigan
Frederick F Lang
Glenn Lesser
Waldemar Debinski
Xuejun Yang
Wei Zhang

Publication Date

4-6-2022

Journal

Molecular Therapy

DOI

10.1016/j.ymthe.2022.02.009

PMID

35151844

PMCID

PMC9077375

PubMedCentral® Posted Date

2-10-2022

PubMedCentral® Full Text Version

Post-print

Abstract

The FGFR3-TACC3 (F3-T3) fusion gene was discovered as an oncogenic molecule in glioblastoma and bladder cancers, and has subsequently been found in many cancer types. Notably, F3-T3 was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment. Here, we show that the F3-T3 protein is a client of heat shock protein 90 (HSP90), forming a ternary complex with the cell division cycle 37 (CDC37). Deprivation of HSP90 or CDC37 disrupts the formation of the ternary complex, which destabilizes glycosylated F3-T3, and thereby suppresses F3-T3 oncogenic activity. Gliomas harboring F3-T3 are resistant to TMZ chemotherapy. HSP90 inhibitors sensitized F3-T3 glioma cells to TMZ via the inhibition of F3-T3 activation and potentiated TMZ-induced DNA damage. These results demonstrate that F3-T3 oncogenic function is dependent on the HSP90 chaperone system and suggests a new clinical option for targeting this genetic aberration in cancer.

Keywords

Carcinogenesis, Cell Cycle Proteins, Cell Line, Tumor, Chaperonins, Glioblastoma, Glioma, HSP90 Heat-Shock Proteins, Humans, Microtubule-Associated Proteins, Molecular Chaperones, Neoplasm Recurrence, Local, Receptor, Fibroblast Growth Factor, Type 3, Temozolomide, FGFR3-TACC3, glioma, HSP90, CDC37, glycosylation, TMZ resistance

Published Open-Access

yes

Recommended Citation

Li, Tao; Mehraein-Ghomi, Farideh; Forbes, M Elizabeth; et al., "HSP90-CDC37 Functions as a Chaperone for the Oncogenic FGFR3-TACC3 Fusion" (2022). Faculty, Staff and Student Publications. 2836.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/2836