Downregulation of BASP1 promotes temozolomide resistance in gliomas via epigenetic activation of the FBXO32/NF-κB/MGMT axis

by Selleckchem | Jul 01 2023

The chemoresistance of temozolomide (TMZ)-based therapy is a serious limitation for lasting effective treatment of gliomas, while the underlying mechanisms remain unclear. In this study, we showed that downregulation of BASP1 correlated negatively with the response to TMZ therapy and disease-free survival of patients with gliomas. Silencing BASP1 significantly enhanced the TMZ-resistance of glioma cells both in vitro and in vivo through repair of TMZ-induced DNA damage via activation of the FBXO32/NF-κB/MGMT axis in both MGMT methylated and unmethylated gliomas. We demonstrated that loss of BASP1 resulted in removal of TRIM37/EZH2 complex-induced repressive histone modifications, including H2A-ub and H3K27me3, but addition of WDR5/MLL complex-mediated active histone modifications, including H3K4me3 and H3K9ac, on the FBXO32 promoter, which elicited in FBXO32 upregulation and further activated NF-κB/MGMT signaling via ubiquitin-dependent degradation of IκBα. Importantly, treatment with OICR-9429, an antagonist of the WDR5-MLL interaction, impaired the FBXO32/NF-κB/MGMT axis-mediated repair of TMZ-induced DNA damage, leading to significant apoptosis of BASP1-downregulated glioma cells. These findings shed light on the molecular mechanism underlying BASP1-mediated epigenetic transcriptional repression and may represent a potential strategy in the fight against TMZ-resistant gliomas. Implications: BASP1 downregulation promotes TMZ resistance in gliomas through WDR5/MLL complex-mediated epigenetic activation of the FBXO32/NF-κB/MGMT axis, providing new target for improving outcomes in patients with TMZ-resistant gliomas.

Comments:

The study you mentioned investigates the chemoresistance of gliomas, particularly in the context of temozolomide (TMZ) therapy, which is commonly used for treating gliomas. The researchers focused on understanding the underlying mechanisms responsible for TMZ resistance and its correlation with BASP1 expression.

The study found that the downregulation of BASP1, a protein, was associated with a negative response to TMZ therapy and reduced disease-free survival in patients with gliomas. Silencing BASP1 was shown to significantly enhance the resistance of glioma cells to TMZ both in laboratory settings (in vitro) and in living organisms (in vivo). The researchers identified that this effect was due to the repair of TMZ-induced DNA damage through the activation of the FBXO32/NF-κB/MGMT axis in both MGMT methylated and unmethylated gliomas.

The loss of BASP1 resulted in the removal of repressive histone modifications, such as H2A-ub and H3K27me3, induced by the TRIM37/EZH2 complex. At the same time, there was an increase in active histone modifications, including H3K4me3 and H3K9ac, mediated by the WDR5/MLL complex, on the FBXO32 promoter. These changes led to upregulation of FBXO32, which further activated the NF-κB/MGMT signaling pathway through the ubiquitin-dependent degradation of IκBα.

To validate the potential therapeutic implications of their findings, the researchers treated BASP1-downregulated glioma cells with OICR-9429, an antagonist that disrupts the interaction between WDR5 and MLL. The treatment impaired the FBXO32/NF-κB/MGMT axis-mediated repair of TMZ-induced DNA damage, resulting in significant apoptosis (cell death) of the BASP1-downregulated glioma cells.

In summary, this study provides insights into the molecular mechanism by which BASP1 downregulation promotes TMZ resistance in gliomas. It highlights the role of the WDR5/MLL complex-mediated epigenetic activation of the FBXO32/NF-κB/MGMT axis in this process. The findings suggest that targeting this pathway, potentially using drugs like OICR-9429, could be a promising strategy to overcome TMZ resistance in gliomas and improve treatment outcomes for patients with resistant gliomas.