Investigation of the modulation of HJURP expression and its relationship with the control of hydroxyurea-induced replicative stress in glioma cells

Abstract

Gliomas are the most common primary brain tumors, with glioblastoma (GBM) being the most common and lethal tumor. Treatment for these tumor types involves surgery, radiotherapy and chemotherapy. However, such combined therapeutic approaches are not widely effective, with tumor advancement and high recurrence rates often occurring. Therefore, genetic characterization is essential for identifying potential biomarkers of prognosis and effective response to treatments. In this scenario, the Holliday Junction Recognizing Protein (HJURP), which is already well described in the literature as a chaperone of centromeric protein A (CENP-A), was demonstrated to be highly expressed and associated with a worse prognosis in several tumor types, including in astrocytomas. Furthermore, the association of HJURP with proteins from the DNA repair pathway through homologous recombination has already been demonstrated, with the maintenance of cell survival and acquisition of radioresistance. Recent data from our group also indicated its potential role in the management of replication stress, a frequent phenomenon in tumor cells and characterized by the slowdown or paralysis of replication forks. It has been seen that astrocytoma cells overexpressing HJURP have greater resistance to replication stress and a lower amount of damage generated. However, interestingly, when cells were treated with hydroxyurea, a drug that induces replication stress, there was a reduction in HJURP expression levels. Therefore, this work aims to induce replicative stress in glioma cells, using hydroxyurea and then characterize the kinetics of HJURP reduction and the impact of such reduction on the stress response and DNA repair, proliferation capacity and cell viability.