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FoxM1-mediated RFC5 expression promotes temozolomide resistance

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Abstract

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.

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Abbreviations

FoxM1:

Forkhead box M1

MGMT:

Methylguanine-DNA methyltransferase

TMZ:

Temozolomide

RFC:

Replication factor C

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Acknowledgements

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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Authors and Affiliations

  1. School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China

    Wan-xin Peng, Xiu Han, Chun-li Zhang, Feng-yi Du, Jie Jin & Ai-hua Gong

  2. Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China

    Lu Ge

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  1. Wan-xin Peng
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  2. Xiu Han
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  3. Chun-li Zhang
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  4. Lu Ge
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  7. Ai-hua Gong
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Correspondence to Ai-hua Gong.

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Peng, Wx., Han, X., Zhang, Cl. et al. FoxM1-mediated RFC5 expression promotes temozolomide resistance. Cell Biol Toxicol 33, 527–537 (2017). https://doi.org/10.1007/s10565-017-9381-1

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