Epigenetic silencing of HTATIP2 in glioblastoma contributes to treatment resistance by enhancing nuclear translocation of the DNA repair protein MPG

Abstract

Glioblastoma, the most malignant brain tumor in adults, exhibits characteristic patterns of epigenetic alterations that await elucidation. The DNA methylome of glioblastoma revealed recurrent epigenetic silencing of HTATIP2, which encodes a negative regulator of importin β‐mediated cytoplasmic–nuclear protein translocation. Its deregulation may thus alter the functionality of cancer‐relevant nuclear proteins, such as the base excision repair (BER) enzyme N‐methylpurine DNA glycosylase (MPG), which has been associated with treatment resistance in GBM. We found that induction of HTATIP2 expression in GBM cells leads to a significant shift of predominantly nuclear to cytoplasmic MPG, whereas depletion of endogenous HTATIP2 results in enhanced nuclear MPG localization. Reduced nuclear MPG localization, prompted by HTATIP2 expression or by depletion of MPG, yielded less phosphorylated‐H2AX‐positive cells upon treatment with an alkylating agent. This suggested reduced MPG‐mediated formation of apurinic/apyrimidinic sites, leaving behind unrepaired DNA lesions, reflecting a reduced capacity of BER in response to the alkylating agent. Epigenetic silencing of HTATIP2 may thus increase nuclear localization of MPG, thereby enhancing the capacity of the glioblastoma cells to repair treatment‐related lesions and contributing to treatment resistance.

PRIM2: A Marker of MYC-driven Hyper-proliferation, Disease Progression, Tumor Aggressiveness and Poor Survival in Glioma Patients

“…Genes associated with metabolic pathways were retrieved from the Mammalian Metabolic Enzyme Database: https://hpcwebapps.cit.nih.gov/ESBL/Database/ MetabolicEnzymes/MetabolicEnzymeDatabase.html. In addition, expression data of glioma patients was also retrieved from GEO database for the following datasets: GSE4290 (21), GSE7696 (22), GSE10878 (23), GSE16011 (24), GSE21354 (25), GSE43289 (26), GSE45921 (27), GSE52009, and GSE107850 (28). Protein expression data of metabolic hits in Clinical Proteomic Tumor Analysis Consortium (CPTAC) database was retrieved from cProcite (https:// cprosite.ccr.cancer.gov/).…”

Temozolomide, Procarbazine and Nitrosoureas in the Therapy of Malignant Gliomas: Update of Mechanisms, Drug Resistance and Therapeutic Implications

“…MPG is found in immunostainings in the cytoplasm and nucleus. High nuclear MPG levels (associated with epigenetic silencing of HTATIP2, a negative regulator of cytoplasmicnuclear translocation) appear to be associated with resistance to methylating agents [154]. Drug screening revealed Sunitinib to be effective in inhibiting MPG, which restored TMZ sensitivity [155], suggesting repurposing the drug in glioma therapy.…”