Dehydroepiandrosterone Induces Temozolomide Resistance Through Modulating Phosphorylation and Acetylation of Sp1 in Glioblastoma

Abstract

Glioblastoma is the most malignant type of brain tumor for which there are currently no effective treatments. Patient prognosis is improved by radiation combined with temozolomide (TMZ) therapy but only for a short period of time due to the high prevalence of recurrence. Although O-methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair is a well-defined characteristic of TMZ resistance, the mechanism by which MGMT-deficient glioblastoma counteracts TMZ-induced DNA damage, leading to apoptosis, still remains unclear. Previously, we determined that aberrantly activated cytochrome P450 17A1 causes TMZ resistance in MGMT-deficient glioblastoma by increasing the secretion of dehydroepiandrosterone (DHEA), a neurosteroid that maintains the health of neurons and astrocytes. However, the precise mechanism by which DHEA alters the response of glioblastoma to TMZ has not been studied. In the present study, we found that DHEA prevents TMZ-induced apoptosis by attenuating DNA damage in MGMT-deficient glioblastoma. In addition, DHEA activated the LYN-AKT cascade to induce Sp1 phosphorylation. Phospho-Sp1 localized in TMZ-damaged DNA, prevented further DNA damage, and was deacetylated through the recruitment of HDAC1/2. Deacetylated Sp1 recruited proliferating cell nuclear antigen (PCNA) to attenuate DNA damage. To confirm whether the DHEA-induced cellular process contributes to TMZ resistance, we established a TMZ-resistant glioblastoma cell line, A172R, and isolated primary resistant tumor cells, PtR#1, from a glioblastoma patient exhibiting chemotherapeutic resistance. Sp1 exhibited phosphorylated and deacetylated status, and associated with HDAC1/2 and PCNA in TMZ-resistant cells. Based on these findings, we conclude that DHEA induces TMZ resistance in glioblastoma via the induction of phospho-Sp1-mediated DNA repair.

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma

“…The PERK, IRE1α, and ATF6α signaling pathways relevant to UPR act as ER stress sensors by binding to ER chaperone Grp78, and remain inactive under normal conditions [21]. However, when unfolded proteins are accumulated in the ER, Grp78 preferentially binds to the unfolded proteins, leading to the release of PERK, IRE1α, and ATF6α.…”

CYP17A1 Maintains the Survival of Glioblastomas by Regulating SAR1-Mediated Endoplasmic Reticulum Health and Redox Homeostasis

“…Previously, we showed that CYP17A1 upregulation confers drug resistance to glioblastomas by increasing DHEA synthesis [7,8]. Hence, we aimed to study whether abiraterone, a well-known CYP17A1 inhibitor [12], potentially suppresses glioblastomas.…”

“…However, brain tumors are also protected by neurosteroids, attenuating the therapeutic effect of chemotherapy. Previously, we found that dehydroepiandrosterone (DHEA), a kind of neurosteroid, protects glioma cells from chemotherapy-induced apoptosis, leading to drug resistance [7,8]. In particular, the upregulation of DHEA in gliomas is caused by Sp1-mediated cytochrome P450 (CYP) 17A1 overexpression [7], implying that CYP17A1 is a potential target for glioma treatment.…”

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

“…TMZ is a common chemotherapeutic drug, and the induction of DNA adducts is primary mechanism of exerting cellular toxicity [24]. Though the administration of TMZ has improved the prognosis of GBM patients, resistance against TMZ was quickly developed [9]. The overexpression of O 6 -methylguanine-DNA-methyltransferase (MGMT) is one of the main resistance mechanisms for repairing O 6 methylguanine, which is an important TMZ-induced lesion resulting in breakage of DNA double-strand and subsequent apoptosis [6,5].…”

“…Although TMZ is considered the most promising chemotherapeutic drug against GBM, most patients suffer from tumor recurrence within 7 months due to the development of resistance [6]. Accumulating evidence demonstrates that the activation of protein kinase B (AKT) is responsible for the evolution of resistance in different types of cancers [7][8][9]. AKT phosphorylates several substrates associated with various cellular processes, such as cell growth, survival and metabolism [10,11].…”