Dehydroepiandrosterone induces Temozolomide Resistance through Attenuating DNA Damage under the Control of Sp1 Phosphorylation and Deacetylation in Glioblastoma

[Speaker] Tsung-I Hsu:1
[Co-author] Jian-Ying Chuang:1, Wen-Chang Chang:1
1:Center for Neurotrauma and Regeneration, Taipei Medical University, Taiwan

Glioblastoma is the most malignant brain tumor without efficiently therapeutic strategy. Improvement of patient prognosis by the combined therapy of radiation with temozolomide (TMZ) is restricted within a small window due to the higher prevalence of recurrence. In particular, O6-methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair is well defined as a characteristic of TMZ resistance, but MGMT-negative glioblastoma still develops an unknown mechanism to counteract TMZ-induced apoptosis. Therefore, the mechanisms underlying the resistance of glioblastoma in response to TMZ-mediated chemotherapy remains controversial. Previously, we clarified that aberrantly activated cytochrome P450 17A1-mediated neurosteroidogenesis caused TMZ resistance in MGMT-deficient glioblastoma through increasing the secretion of dehydroepiandrosterone (DHEA), which maintains the health of neurons and astrocytes in addition to being an adrenal gland-secreted steroid hormone. However, how DHEA alters the response of glioblastoma to TMZ has not been studied. In this study, we found that DHEA prevented TMZ-induced apoptosis through attenuating DNA damage characterized by the comet assay, apurinic/apyrimidinic site detection and γH2Ax expression in MGMT-deficient glioblastoma. In addition, DHEA activated the Lyn-Akt cascade to induce Sp1 phosphorylation which localized in TMZ-damaged DNA and was responsible to prevent DNA damage. Furthermore, p-Sp1 was deacetylated through the recruitment of HDAC1/2, and deacetylated Sp1 recruited proliferating cell nuclear antigen (PCNA) to attenuating DNA damage. To confirm whether DHEA-induced cellular process contributes to TMZ resistance, we established TMZ-resistant glioblastoma cells, A172-R. In addition to phosphorylation and deacetylation, the association of Sp1 with HDAC1/2 and PCNA was identified in A172-R, not in wild-type A172 cells. Based on these findings, we conclude that DHEA induces TMZ resistance in glioblastoma through inducing phospho-Sp1-mediated DNA repair.
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