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Sci Rep. 2016 Dec 21;6:39743. doi: 10.1038/srep39743.

BACH1 Promotes Temozolomide Resistance in Glioblastoma through Antagonizing the Function of p53.

Nie E1, Jin X1, Wu W1, Yu T1, Zhou X1, Zhi T1, Shi Z1,2, Zhang J1, Liu N1,3, You Y1,3.

Author information

1
Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
2
State Key lab of Reproductive Medicine, Department of Pathology, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing 210029, China.
3
Chinese Glioma Cooperative Group (CGCG), Nanjing, China.

Abstract

The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that BACH1, a heme-binding protein that participates in transcriptional repression or activation, was significantly upregulated in glioblastoma tissues. Overexpression of BACH1 in GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in vivo. Further investigation revealed that BACH1 activation significantly enhanced the expression of MGMT, and depletion of p53 disrupted the effects of BACH1 on MGMT and temozolomide resistance. P53 sequesters SP1 to prevent its binding to the MGMT promoter region and thus inhibits MGMT expression. Moreover, BACH1 overexpression impaired the association between p53 and SP1 via competitive binding p53, and antagonized the impact of p53 on MGMT expression. Finally, we found that BACH1 low expression correlated with better prognosis in GBM patients undergoing temozolomide therapy, especially in patients with wild-type TP53. Collectively, our findings identify a potential mechanism by which wild-type TP53 GBM cells develop resistance to temozolomide and suggest that targeting this pathway may be beneficial for overcoming resistance.

PMID:
28000777
PMCID:
PMC5175153
DOI:
10.1038/srep39743
[Indexed for MEDLINE]
Free PMC Article

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