Acquired temozolomide resistance in MGMT-deficient glioblastoma cells is associated with regulation of DNA repair by DHC2

Author:

Yi Guo-zhong12,Huang Guanglong13,Guo Manlan2,Zhang Xi’an1,Wang Hai1,Deng Shengze1,Li Yaomin1,Xiang Wei14,Chen Ziyang1,Pan Jun1,Li Zhiyong1,Yu Lei1,Lei Bingxi1,Liu Yawei2,Qi Songtao15

Affiliation:

1. Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, People’s Republic of China

2. The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, People’s Republic of China

3. Department of Neurosurgery, Longgang Central Hospital of Shenzhen, Shenzhen 518116, Guangdong, People's Republic of China

4. Department of Neurosurgery, The First Affliated Hospital, Southwest Medical University, Luzhou 646000, Sichuan, People’s Republic of China

5. Nanfang Glioma Center, Guangzhou 510515, Guangdong, People’s Republic of China

Abstract

Abstract The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by O6-methylguanine-DNA methyltransferase (MGMT). However, some MGMT-deficient glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DYNC2H1 (DHC2) was expressed more in MGMT-deficient recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT promotor methylated glioblastoma patients. Furthermore, silencing DHC2, both in vitro and in vivo, enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-deficient glioblastoma. Using a combination of subcellular proteomics and in vitro analyses, we showed that DHC2 was involved in nuclear localization of the DNA repair proteins, namely XPC and CBX5, and knockdown of either XPC or CBX5 resulted in increased temozolomide-induced DNA damage. In summary, we identified the nuclear transportation of DNA repair proteins by DHC2 as a critical regulator of acquired temozolomide resistance in MGMT-deficient glioblastoma. Our study offers novel insights for improving therapeutic management of MGMT-deficient glioblastoma.

Funder

National Natural Science Foundation of China

Guangdong Science and Technology Department

Publisher

Oxford University Press (OUP)

Subject

Clinical Neurology

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