A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma

Xiaoyue Chen, Minjie Zhang, Haiyun Gan, Heping Wang, Jeong-Heon Lee, Dong Fang, Gaspar J. Kitange, Lihong He, Zeng Hu, Ian F. Parney, Fredric B. Meyer, Caterina Giannini, Jann N. Sarkaria () and Zhiguo Zhang ()
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Xiaoyue Chen: Mayo Clinic
Minjie Zhang: Columbia University
Haiyun Gan: Columbia University
Heping Wang: Huazhong University of Science and Technology
Jeong-Heon Lee: Mayo Clinic
Dong Fang: Columbia University
Gaspar J. Kitange: Mayo Clinic
Lihong He: Mayo Clinic
Zeng Hu: Mayo Clinic
Ian F. Parney: Mayo Clinic
Fredric B. Meyer: Mayo Clinic
Caterina Giannini: Mayo Clinic
Jann N. Sarkaria: Mayo Clinic
Zhiguo Zhang: Columbia University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Temozolomide (TMZ) was used for the treatment of glioblastoma (GBM) for over a decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that an enhancer, located between the promoters of marker of proliferation Ki67 (MKI67) and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines and recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to a dramatic reduction of MGMT and a lesser extent of Ki67 expression, increased TMZ sensitivity, and impaired proliferation. Together, these studies uncover a mechanism that regulates MGMT expression, confers TMZ resistance, and potentially regulates tumor proliferation.

Date: 2018
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DOI: 10.1038/s41467-018-05373-4

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