Valproic acid enhances temozolomide efficacy via epigenetic Upregulation of miR-124-3p and Suppression of Sp1 in glioma.

Authors

Elyar Mahboubi, Mehdi Sadegh, Behzad Khansarinejad, Mahdieh Mondanizadeh, Mohammad Hasan Sakhaie

Published in

Gene. Pages 150493. Nov 12, 2026. Epub Nov 12, 2026.

Abstract

Gliomas are aggressive brain tumors with poor prognosis and limited responsiveness to temozolomide (TMZ). Valproic acid (VPA), a histone deacetylase inhibitor, has shown epigenetic modulatory effects in various cancers. This study investigated whether VPA enhances TMZ efficacy through epigenetic modulation of the miR-124-3p/Sp1 regulatory axis in a rat glioma model.
C6 glioma cells were treated with TMZ and VPA, and cell viability was assessed by MTT assay. In vivo, C6 cells were stereotaxically implanted into the striatum of 60 male Wistar rats. Animals were divided into six groups: intact, sham, glioma, glioma + TMZ (8 mg/kg), glioma + VPA (300 mg/kg), and glioma + TMZ + VPA. Treatments started on day 14 post-implantation, and animals were evaluated on day 24. Brain tissues were analyzed by Nissl staining and quantitative real-time PCR for miR-124-3p and Sp1 expression. To confirm the direct regulatory interaction between miR-124-3p and Sp1, a dual-luciferase reporter assay was performed in C6 glioma cells using the Sp1 3'-UTR containing the putative miR-124-3p binding site.
Both TMZ and VPA reduced C6 cell viability, with the combination producing a greater inhibitory effect. In glioma-bearing rats, miR-124-3p expression decreased significantly, whereas Sp1 expression increased compared with controls. TMZ or VPA partially corrected these changes, while combined treatment produced the greatest increase in miR-124-3p (2.09-fold) and reduction in Sp1 (1.18-fold). A significant negative correlation was observed between miR-124-3p and Sp1 (r =  - 0.59, P < 0.0001). Histopathological findings qualitatively supported the molecular results. Mechanistically, a luciferase reporter assay confirmed that miR-124-3p directly targets the Sp1 3'-UTR, validating the regulatory interaction.
Combined VPA and TMZ treatment was associated with greater modulation of the miR-124-3p/Sp1 axis than either monotherapy. These findings support potential involvement of this regulatory axis in treatment response and warrant further investigation of its value as a biomarker and potential therapeutic target in glioma. More broadly, the findings provide a rationale for investigating small RNA-based therapeutic strategies targeting dysregulated regulatory pathways in glioma. However, the therapeutic efficacy of miR-124-3p-based interventions and the contribution of epigenetic mechanisms to the observed molecular changes remain to be established.

PMID:
43020189
Bibliographic data and abstract were imported from PubMed on 13 Nov 2026.

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