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Silencing SATB1 overcomes temozolomide resistance by downregulating MGMT expression and upregulating SLC22A18 expression in human glioblastoma cells

Cancer Gene Therapy volume 25, pages 309–316 (2018)Cite this article

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Abstract

Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system and has a very poor prognosis. Currently, patients were treated by resection followed by radiotherapy plus concurrent temozolomide (TMZ) chemotherapy. However, many patients are resistant to TMZ-induced DNA damage because of upregulated expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). In this study, upregulation of SATB1 and MGMT, and downregulation of SLC22A18 resulted in acquisition of TMZ resistance in GBM U87 cells. Inactivation of special AT-rich sequence-binding protein 1 (SATB1) using short hairpin RNA (shRNA) downregulated MGMT expression and upregulated solute carrier family 22 member 18 (SLC22A18) expression in GBM cells. This suggested SATB1-mediated posttranscriptional regulation of the MGMT and SLC22A18 protein levels. Immunohistochemical analysis of malignant glioma specimens demonstrated a significant positive correlation between the levels of MGMT and SATB1, and a negative correlation between the levels of SLC22A18 and SATB1. Importantly, in recurrent, compared with the primary, lesions in 15 paired identical tumors, the SATB1 and MGMT protein levels were increased and the SLC22A18 levels were decreased. Finally, in TMZ-resistant GBM, SATB1 knockdown enhanced TMZ efficacy. Consequently, SATB1 inhibition might be a promising strategy combined with TMZ chemotherapy to treat TMZ-resistant GBM.

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Acknowledgements

This work was supported by grants from the Scientific Research Foundation for the Returned Overseas Chinese Scholars (082003), the Research Foundation of Shanghai Municipal Health and Family Planning Commission (201540266), the Shanghai Jiao Tong University Medicine-Engineering Cross Research Foundation (YG2015MS25) and the Research Foundation of Shanghai No. 3 People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (syz2015-015).

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  1. Department of Neurosurgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, China

    Biao Yang, Yan-Bin Ma & Sheng-Hua Chu

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  1. Biao Yang
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Correspondence to Sheng-Hua Chu.

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Yang, B., Ma, YB. & Chu, SH. Silencing SATB1 overcomes temozolomide resistance by downregulating MGMT expression and upregulating SLC22A18 expression in human glioblastoma cells. Cancer Gene Ther 25, 309–316 (2018). https://doi.org/10.1038/s41417-018-0040-3

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