title: Epigenetic targeting of glioma stem cells: Short-term and long-term treatments with valproic acid modulate DNA methylation and differentiation behavior, but not temozolomide sensitivity.
abstract: Glioblastoma (GBM) is the most aggressive tumor of the central nervous system. GBM is a fatal tumor, incurable by conventional therapies. One of the factors underlying tumor recurrence and poor long-term survival is the presence of a cancer stem-like cell population, termed glioma stem cells (GSCs), which is particularly resistant to chemotherapy and radiotherapy and supports tumor self-renewal. The aim of the present study was to evaluate the impact and difference in effects of short-term and long‑term treatments with valproic acid (VPA), a histone deacetylase inhibitor, on seven GSC lines. We investigated for the first time the changes in the genome-wide DNA methylation profile and the differentiation behavior of GSCs induced by short-term and long-term VPA treatments. Moreover, we verified VPA sensitivity after long-term VPA pretreatment and, notably, the results provide evidence of a subpopulation more resistant to further VPA treatments. Finally, since short-term VPA treatment induced a reversal of the MGMT methylation status, we aimed to sensitize GSCs to temozolomide, the drug commonly used for this tumor, using this regimen. The overall data highlighted the heterogeneous behavior of GSC lines that is representative of tumor heterogeneity in GBM. The VPA effects were variable among these cell lines in terms of pro‑differentiating ability and DNA methylation switch. Here, we attempted to identify a suitable therapy for the eradication of the stem cell subpopulation, which is mandatory to achieve an effective treatment for this tumor. Differentiation-inducing and epigenetic therapies are the most promising approaches to affect the multiple properties of GSCs and, finally, defeat GBM.
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, I-20900 Monza, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Riva
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, I-20900 Monza, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Butta
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, I-20900 Monza, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cilibrasi
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, I-20900 Monza, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Baronchelli
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, I-20900 Monza, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Redaelli
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, I-20900 Monza, Italy.
authors.forename: Leda
authors.initials: L
authors.lastname: Dalprà
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, I-20900 Monza, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Lavitrano
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, I-20900 Monza, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Bentivegna
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D019175:DNA Methylation; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D011401:Promoter Regions, Genetic; D000077204:Temozolomide; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D003606:Dacarbazine; D000077204:Temozolomide