CUL4B Promotes Temozolomide Resistance in Gliomas by Epigenetically Repressing CDNK1A Transcription

Abstract

Resistance to temozolomide (TMZ), the first-line chemotherapeutic drug for glioblastoma (GBM) and anaplastic gliomas, is one of the most significant obstacles in clinical treatment. TMZ resistance is regulated by complex genetic and epigenetic networks. Understanding the mechanisms of TMZ resistance can help to identify novel drug targets and more effective therapies. CUL4B has been shown to be upregulated and promotes progression and chemoresistance in several cancer types. However, its regulatory effect and mechanisms on TMZ resistance have not been elucidated. The aim of this study was to decipher the role and mechanism of CUL4B in TMZ resistance. Western blot and public datasets analysis showed that CUL4B was upregulated in glioma specimens. CUL4B elevation positively correlated with advanced pathological stage, tumor recurrence, malignant molecular subtype and poor survival in glioma patients receiving TMZ treatment. CUL4B expression was correlated with TMZ resistance in GBM cell lines. Knocking down CUL4B restored TMZ sensitivity, while upregulation of CUL4B promoted TMZ resistance in GBM cells. By employing senescence β-galactosidase staining, quantitative reverse transcription PCR and Chromatin immunoprecipitation experiments, we found that CUL4B coordinated histone deacetylase (HDAC) to co-occupy the CDKN1A promoter and epigenetically silenced CDKN1A transcription, leading to attenuation of TMZ-induced senescence and rendering the GBM cells TMZ resistance. Collectively, our findings identify a novel mechanism by which GBM cells develop resistance to TMZ and suggest that CUL4B inhibition may be beneficial for overcoming resistance.

Repurposed Drugs Celecoxib and Fmoc-L-Leucine Alone and in Combination as Temozolomide-Resistant Antiglioma Agents—Comparative Studies on Normal and Immortalized Cell Lines, and on C. elegans

“…The U-118 MG glioma cell line is described as being resistant to TMZ up to 100 µM, or even 250 µM concentration, after 24 and 48 h incubation [ 32 , 33 , 34 ]. Our cytotoxicity studies confirmed that TMZ had no effect on the viability of these cells after 24 h incubation in the range of 25–200 µM concentration.…”

Evidence That a Peptide-Drug/p53 Gene Complex Promotes Cognate Gene Expression and Inhibits the Viability of Glioblastoma Cells

“…As SNB19 and U373 cells are resistant to TMZ action and TMZ-loaded complexes were not the ones decreasing SNB19 and U373 cellular viability the most and given that these complexes were able to promote activation of caspases, most probably, a senescence phenomenon took place in these cells due to TMZ treatment. According to published studies, TMZ drug can induce apoptosis, but it also activates survival pathways such as senescence [ 98 , 99 ]. Considering that MGMT protein may exert an important role in TMZ resistance, it would be advantageous to test MGMT expression in the investigated cell lines [ 34 , 100 ].…”

“…activation of caspases, most probably, a senescence phenomenon took place in these due to TMZ treatment. According to published studies, TMZ drug can induce apop but it also activates survival pathways such as senescence [98,99]. Considering that M protein may exert an important role in TMZ resistance, it would be advantageous t MGMT expression in the investigated cell lines [34,100].…”

Curzerene suppresses progression of human glioblastoma through inhibition of glutathione S‐transferase A4

“…4,5 Chemotherapy is an important adjuvant treatment for glioma, but the efficacy of traditional first-line chemotherapy drugs, including temozolomide, in glioma cases is less than 60%, and their toxicity and side-effect profiles bring an additional health burden to patients. 6 Because of unsatisfactory results with front-line agents, some researchers have begun to explore the inhibitory effects of traditional Chinese medicines on tumors. Some traditional Chinese medicines have been proven not only to lead to lower decreases in patient quality of life, but also to have considerable potent anticancer effects.…”