491P - SRSF7 promotes glioblastoma progression via CDK1-mediated G2/M phase arrest of GBM cells

Background

Glioblastoma (GBM) is characterized by high malignancy, high recurrence, and poor prognosis. The underlying mechanisms of GBM progression remain largely elusive. SRSF7 (serine/arginine-rich splicing factor 7), a member of the SRSF family, albeit serves as a potential therapeutic target in other solid tumours, although the role in GBM progression is still unknown.

Methods

Firstly, IHC assays were used to clarify the correlation between SRSF7 and the malignancy of GBM, as well as the prognosis of GBM patients. Secondly, scRNA-seq analysis displayed that SRSF7 was mainly expressed in GBM cell, while SRSF7 knockdown in GBM cells were conducted to identify that SRSF7 was significant in maintaining the GBM cell cycle. Subsequently, RNA-seq showed that SRSF7 regulated the G2/M phase of GBM cells via CDK1; Co-IP, RIP, IF, and nuclear plasma separation assays were performed to elucidate the mechanism of SRSF7 and CDK1. Finally, the orthotopic implantation GBM models were conducted to trace the therapeutic effect of inhibition of SRSF7, combined with CDK1 inhibitor in vivo.

Results

We first observed that SRSF7 was positively correlated with the malignancy of gliomas, as well as the poor prognosis of GBM patients. As a result, it was found that SRSF7 promoted GBM progression by arresting the G2/M phase of GBM cells, either in vitro or in vivo. Mechanistically, we identified that SRSF7 regulated cyclin-dependent kinase 1 (CDK1) expression by RNA alternative splicing in the nucleus, as well as CDK1 abrogation could inhibit the phosphorylation of SRSF7, which promote the nuclear translocation of SRSF7, thereby increasing the ubiquitinate degradation of SRSF7. Then, the stagnating G2/M in GBM cells, caused by SRSF7 knockdown, could be rescued by CDK1 overexpression. Finally, the orthotopic GBM models showed that the inhibition of SRSF7, combined with CDK1 inhibitor, could attenuate GBM progression, and prolong the survival time of tumour-bearing mice.

Conclusions

These results provided direct evidences that SRSF7 acts as the oncogene in GBM development. And there is a positive feedback loop between SRSF7 and CDK1, which collaboratively promote GBM progression. The study suggests that combined inhibition of SRSF7 and CDK1 may serve as a new approach for GBM therapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The Second Affiliate Hospital of Air Force Medical University/Tangdu Hospital Neurosurgery.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.