Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

J-Y Chuang; W-L Lo; C-Y Ko; S-Y Chou; R-M Chen; K-Y Chang; J-J Hung; W-C Su; W-C Chang; T-I Hsu

doi:10.1038/oncsis.2017.31

Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

Oncogenesis. 2017 May 22;6(5):e339. doi: 10.1038/oncsis.2017.31.

Authors

J-Y Chuang^{1

2}, W-L Lo^{1

3}, C-Y Ko^{1

2}, S-Y Chou^{1

2}, R-M Chen^{2

4}, K-Y Chang⁵, J-J Hung⁶, W-C Su⁷, W-C Chang^{1

2

4}, T-I Hsu^{1

2

8}

Affiliations

¹ The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan.
² Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan.
³ Division of Neurosurgery, Taipei Medical University-Shuang-Ho Hospital, Taipei, Taiwan.
⁴ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁵ National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
⁶ Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
⁷ Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
⁸ Center for Neurotrauma and Neuroregeneration, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

Abstract

Steroidogenesis-mediated production of neurosteroids is important for brain homeostasis. Cytochrome P450 17A1 (CYP17A1), which converts pregnenolone to dehydroepiandrosterone (DHEA) in endocrine organs and the brain, is required for prostate cancer progression and acquired chemotherapeutic resistance. However, whether CYP17A1-mediated DHEA synthesis is involved in brain tumor malignancy, especially in glioma, the most prevalent brain tumor, is unknown. To investigate the role of CYP17A1 in glioma, we determined that CYP17A1 expression is significantly increased in gliomas, which secrete more DHEA than normal astrocytes. We found that as gliomas became more malignant, both CYP17A1 and DHEA were significantly upregulated in temozolomide (TMZ)-resistant cells and highly invasive cells. In particular, the increase of CYP17A1 was caused by Sp1-mediated DNA demethylation, whereby Sp1 competed with DNMT3a for binding to the CYP17A1 promoter in TMZ-resistant glioma cells. CYP17A1 was required for the development of glioma cell invasiveness and resistance to TMZ-induced cytotoxicity. In addition, DHEA markedly attenuated TMZ-induced DNA damage and apoptosis. Together, our results suggest that components of the Sp1-CYP17A1-DHEA axis, which promotes the development of TMZ resistance, may serve as potential biomarkers and therapeutic targets in recurrent glioma.