Phragmunis a suppresses glioblastoma through the regulation of MCL1-FBXW7 by blocking ELK1-SRF complex-dependent transcription.

Glioblastoma (GBM) is a highly aggressive brain tumor. During screening work, we found a new compound named phragmunis A (PGA), which is derived from the fruitbody of Trogia venenata, exhibits a potential cytotoxic effect on patient-derived recurrent GBM cells and temozolomide (TMZ)-resistant cell lines. The present study was designed to investigate the potential molecular mechanism of the anti-glioma effects of PGA in vitro and in vivo. Studies investigating the mechanism revealed that PGA diminished the binding efficiency of ETS family of transcription factor (ELK1) and Serum response factor (SRF), and suppressed ELK1-SRF complex-dependent transcription, which decreased the transcriptional levels of downstream genes Early growth response protein 1 (EGR1)-Polycomb ring finger (BMI1), thus inducing the imbalanced regulation between Myeloid cell leukaemia-1 (MCL1) and F-Box and WD repeat domain containing 7 (FBXW7). Finally, orthotopic xenograft models were established to confirm the anti-glioma effect of PGA on tumour growth. We showed, for the first time, that the cytotoxic effects of PGA occurred by inducing MCL1 inhibition and FBXW7 activation by blocking ELK1-SRF complex-dependent transcription. The blockage of ELK1-mediated transcription resulted in the suppression of EGR1-BMI1, which led to the upregulation of FBXW7 expression and downregulation of MCL1. These findings suggested that PGA could be a therapeutic drug candidate for the treatment of recurrent GBM by targeting the ELK1-SRF complex.

Blocking miR-27a-3p sensitises Taxol resistant osteosarcoma cells through targeting Fbxw7.

Osteosarcoma (OS) is a human malignancy, which primarily affects the long bones and occurs in children and adolescent. Although advanced clinical approaches and the addition of neoadjuvant chemotherapy improved 5-year survival of OS patients, a large fraction of them developed chemoresistance. Thus, due to the high morbidity and mortality of OS, it is urgent to investigate effectively molecular targets against chemoresistant osteosarcoma. In this study, we aimed to evaluate the functions of miR-27a-3p in the Taxol sensitivity of osteosarcoma. From fifty-paired OS tumour tissues and adjacent normal bone tissues, we detected significantly upregulated miR-27a-3p expressions in osteosarcoma. In addition, expression of miR-27a-3p was remarkedly elevated in OS cancer cell lines compared with normal osteoblast cells, hFOB1.19. Blocking miR-27a-3p effectively suppressed OS cell growth and sensitised OS cells to Taxol. miRNA target prediction indicated Fbxw7 was a potential target of miR-27a-3p. We demonstrated Fbxw7 functioned as a tumour suppressor in osteosarcoma. Overexpression of miR-27a-3p significantly suppressed Fbxw7 protein expression in OS cells. The direct binding between miR-27a-3p and Fbxw7 3'UTR was validated by luciferase assay. Particularly, results from rescue experiments by inhibiting Fbxw7 expressions in miR-23a-3p-blocked OS cells demonstrated the miR-27a-3p-mediated Taxol resistance was through direct targeting Fbxw7. In summary, our findings report a new molecular mechanism for the miR-27a-3p-mediated Taxol resistance via targeting tumour suppressor, Fbxw7 in osteosarcoma. This study potentiates a miRNA-based therapeutic approach against Taxol resistant osteosarcoma.