ZEB1 is a Subgroup-Specific Marker of Prognosis and Potential Drug Target in Medulloblastoma.

Livia Fratini, Matheus Gibeke Siqueira Dalmolin, Marialva Sinigaglia, Alexandre da Silveira Perla, Caroline Brunetto de Farias, Algemir L Brunetto, André T Brunetto, Mariane da Cunha Jaeger, Rafael Roesler

Journal: Neuromolecular medicine 2023;25(1):64-74

PMID: 35716340

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Abstract

Medulloblastoma (MB) is a malignant brain tumor that afflicts mostly children and adolescents and presents four distinct molecular subgroups, known as WNT, SHH, Group 3, and Group 4. ZEB1 is a transcription factor that promotes the expression of mesenchymal markers while restraining expression of epithelial and polarity genes. Because of ZEB1 involvement in cerebellum development, here we investigated the role of ZEB1 in MB. We found increased expression of ZEB1 in MB tumor samples compared to normal cerebellar tissue. Expression was higher in the SHH subgroup when compared to all other MB molecular subgroups. High ZEB1 expression was associated with poor prognosis in Group 3 and Group 4, whereas in patients with WNT tumors poorer prognosis were related to lower ZEB1 expression. There was a moderate correlation between ZEB1 and MYC expression in Group 3 and Group 4 MB. Treatment with the immunomodulator and histone deacetylase (HDAC) inhibitor fingolimod (FTY720) reduced ZEB1 expression specifically in D283 cells, which are representative of Group 3 and Group 4 MB. These findings reveal novel subgroup-specific associations of ZEB1 expression with survival in patients with MB and suggest that ZEB1 expression can be reduced by pharmacological agents that target HDAC activity.

Address: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil. [email protected].; Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil. [email protected].; Graduate Program in Cellular and Molecular Biology, Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, RS, 91501-970, Brazil. [email protected].; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.; Children's Cancer Institute, Porto Alegre, RS, 90620-110, Brazil.; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.; Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil.; Neurology Service, São José Hospital, Santa Casa de Misericórdia Porto Alegre Hospital Complex, Porto Alegre, RS, 90020-090, Brazil.; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil. [email protected].; Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, 90050-170, Brazil. [email protected].; Graduate Program in Cellular and Molecular Biology, Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, RS, 91501-970, Brazil. [email protected].

DOI: 10.1007/s12017-022-08716-z

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https://dx.doi.org/10.1007/s12017-022-08716-z

MeSH Terms: Child, Adolescent, Humans, Medulloblastoma, Brain Neoplasms, Cerebellum, Histone Deacetylase Inhibitors, Fingolimod Hydrochloride, Cerebellar Neoplasms, Zinc Finger E-box-Binding Homeobox 1