FoxM1-mediated RFC5 expression promotes temozolomide resistance
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Although methylguanine-DNA-methyltransferase (MGMT) plays an important role in resistance to temozolomide (TMZ) in glioma, 40% of gliomas with MGMT inactivation are still resistant to TMZ. The underlying mechanism is not clear. Here, we report that forkhead box M1 (FoxM1) transcriptionally activates the expression of DNA repair gene replication factor C5 (RFC5) to promote TMZ resistance in glioma cells independent of MGMT activation. We showed that RFC5 expression is positively correlated with FoxM1 expression in human glioma cells and FoxM1 is able to transcriptionally activate RFC expression by interaction with the RFC5 promoter. Furthermore, knockdown of FoxM1 or RFC5 partially re-sensitizes glioma cells to TMZ. Consistently, thiostrepton, a FoxM1 inhibitor, in combination with TMZ significantly inhibits proliferation and promotes apoptosis in glioma cells. Taken together, these findings suggest that the FoxM1-RFC5 axis may mediate TMZ resistance and thiostrepton may serve as a potential therapeutic agent against TMZ resistance in glioma cells.
KeywordsGlioma Chemo-resistance FoxM1 RFC5 TMZ
Forkhead box M1
Replication factor C
This work was supported by grants from the Natural Science Foundation of China (81372718 to A.G.; 31100964 to W.P.), Postdoctoral Science Foundation Funded Project by Jiangsu province (1402102C to W.P.), and the Specialized Research Fund for Senior Personnel Program of Jiangsu University (10JDG45 to W.P.).
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Conflict of interest
The authors declare that they have no conflict of the interest.
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