In a recent study published in Genes & Diseases, researchers from Chinese Academy of Medical Sciences and Peking Union Medical College, Capital Medical University, and China International Neuroscience Institute (China-INI) investigated the molecular mechanisms underlying this resistance, identifying heat shock protein 90B1 (HSP90B1) as a critical regulator of glioma progression and radioresistance.
Heat shock proteins (HSPs) function as molecular chaperones that maintain protein stability under stress conditions; however, their specific contributions to glioma pathology and therapeutic resistance remain elusive.
Through integrative analyses of patient datasets from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), the study identified HSP90B1 as significantly upregulated in glioma and strongly associated with poor prognosis in patients undergoing radiotherapy, with expression levels correlating directly with tumor malignancy and unfavorable survival outcomes.
Functional experiments in glioma cell lines further demonstrated that HSP90B1 enhances tumor cell proliferation, migration, and invasion, while simultaneously protecting cells from radiotherapy-induced apoptosis by modulating key DNA damage repair factors, including γH2AX and RAD50. By enhancing these repair mechanisms, HSP90B1 enables glioma cells to survive the lethal double-strand breaks typically induced by ionizing radiation, thereby promoting tumor survival under therapeutic stress.
Mechanistically, co-immunoprecipitation (Co-IP) and rescue experiments revealed that HSP90B1 directly interacts with the RhoC protein, preventing its ubiquitin–proteasome-mediated degradation and thereby stabilizing its expression, sustaining its pro-tumorigenic functions. In the absence of this protective interaction, RhoC undergoes ubiquitination and subsequent proteasomal degradation, leading to reduced tumor cell motility and increased sensitivity to radiotherapy.
The therapeutic implications of this axis were further validated using a xenograft mouse model, where tumors overexpressing HSP90B1 exhibited significantly accelerated growth and diminished responsiveness to localized radiation therapy. Immunohistochemical analysis of harvested tumors revealed that high levels of both HSP90B1 and RhoC were associated with elevated expression of the proliferation marker Ki-67 despite radiation treatment, confirming their role in mediating therapeutic resistance. Conversely, targeting HSP90B1 disrupts RhoC stabilization, thereby impairing tumor progression and restoring radiosensitivity. These findings highlight a previously unrecognized regulatory axis in which HSP90B1 promotes glioma aggressiveness by maintaining RhoC expression through inhibition of ubiquitin-mediated degradation.
In conclusion, this study provides compelling evidence that HSP90B1 serves as a key driver of glioma radiotherapy resistance by stabilizing RhoC and sustaining metastatic and survival signaling pathways, thereby identifying the HSP90B1–RhoC axis as a promising therapeutic target for overcoming radioresistance and improving clinical outcomes in glioma patients.
Reference
Title of the original paper: HSP90B1 facilitates glioma radiotherapy resistance by regulating RhoC ubiquitin‒proteasome degradation
Journal : Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI : https://doi.org/10.1016/j.gendis.2025.101756
