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; Zhiguo Zhang

doi:10.1038/s41467-018-05373-4

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

Nat Commun. 2018 Jul 27;9(1):2949. doi: 10.1038/s41467-018-05373-4.

Authors

Xiaoyue Chen¹, Minjie Zhang², Haiyun Gan², Heping Wang³, Jeong-Heon Lee¹, Dong Fang², Gaspar J Kitange⁴, Lihong He⁴, Zeng Hu⁴, Ian F Parney⁵, Fredric B Meyer⁵, Caterina Giannini⁶, Jann N Sarkaria⁷, Zhiguo Zhang⁸

Affiliations

¹ Biochemistry and Molecular Biology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
² Institute for Cancer Genetics, Department of Pediatrics and Department of Genetics and Development, Irving Cancer Research Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY, 10032, USA.
³ Department of Neurosurgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jie Fang Avenue, Hankou, 430030, Wuhan, China.
⁴ Department of Radiation Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
⁵ Department of Neurologic Surgery, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
⁷ Department of Radiation Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA. [email protected].
⁸ Institute for Cancer Genetics, Department of Pediatrics and Department of Genetics and Development, Irving Cancer Research Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY, 10032, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Biomarkers, Tumor
Cell Line, Tumor
Cell Proliferation / drug effects
Clustered Regularly Interspaced Short Palindromic Repeats / genetics
DNA Methylation
DNA Modification Methylases / genetics*
DNA Modification Methylases / metabolism*
DNA Repair Enzymes / genetics*
DNA Repair Enzymes / metabolism*
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
E1A-Associated p300 Protein / genetics
Gene Deletion
Gene Expression Regulation, Neoplastic / drug effects*
Gene Expression Regulation, Neoplastic / genetics*
Glioblastoma / genetics*
Glioblastoma / metabolism*
HEK293 Cells
Heterografts
Humans
Ki-67 Antigen / genetics
Ki-67 Antigen / metabolism
Promoter Regions, Genetic / genetics
Temozolomide / pharmacology*
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism*

Substances

Biomarkers, Tumor
Ki-67 Antigen
MKI67 protein, human
Tumor Suppressor Proteins
DNA Modification Methylases
MGMT protein, human
E1A-Associated p300 Protein
EP300 protein, human
DNA Repair Enzymes
Temozolomide

Abstract

Publication types

MeSH terms

Substances

Grants and funding