Glioma–astrocyte connexin43 confers temozolomide resistance through activation of the E2F1/ERCC1 axis

Abstract Background Glioma is the most prevalent and lethal tumor of the central nervous system. Routine treatment with temozolomide (TMZ) would unfortunately result in inevitable recurrence and therapy resistance, severely limiting therapeutic efficacy. Tumor-associated astrocytes (TAAs) are key components of the tumor microenvironment and increasing evidence has demonstrated that aberrant expression of connexin43 (Cx43) was closely associated with glioma progression and TMZ resistance. However, the specific role of Cx43 in mediating TMZ resistance through glioma and astrocyte interactions has not been fully explored. Methods The expression and prognostic value of Cx43 were evaluated in tumor samples and clinical databases. ShRNA-medicated knockdown and Gfap-Cre Cx43flox/flox gene mouse were used to assess the role and functional significance of Cx43 in vitro and in vivo. Moreover, we performed mass spectrometry analysis, chromatin immunoprecipitation, and other biochemical assays to define the molecular mechanisms by which Cx43 promotes TMZ resistance. Results We confirmed that the upregulation of Cx43 expression between TAAs and glioma cells contributed to TMZ resistance and tumor recurrence. Genetic knockdown or pharmacological inhibition of Cx43 enhanced TMZ-induced cytotoxicity. Mechanistically, elevated Cx43 expression induced β-catenin accumulation at the cell surface of glioma cells, suppressing T-cell factor/lymphoid enhancer-binding factor transcription. This led to impaired miR-205-5p expression and subsequent activation of the E2F1/ERCC1 axis, which eventually led to chemoresistance. Conclusions Our study reveals a novel regulatory mechanism in which the Cx43/miR-205-5p/E2F1/ERCC1 axis contributes to TMZ resistance in glioma. These findings further highlight the potential of targeting Cx43 as a therapeutic strategy in glioma.