Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma

Harish Shrikrishna Bharambe,Kedar Yogi,Annada Joshi,Neelam Vishwanath Shirsat,Sadaf Kazi

doi:10.1186/s40478-020-00942-5

Abstract

Medulloblastoma, a highly malignant pediatric brain tumor, consists of four molecular subgroups, namely WNT, SHH, Group 3, and Group 4. The expression of miR-193a, a WNT subgroup-specific microRNA, was found to be induced by MYC, an oncogenic target of the canonical WNT signaling. MiR-193a is not expressed in Group 3 medulloblastomas, despite MYC expression, as a result of promoter hypermethylation. Restoration of miR-193a expression in the MYC amplified Group 3 medulloblastoma cells resulted in inhibition of growth, tumorigenicity, and an increase in radiation sensitivity. MAX, STMN1, and DCAF7 were identified as novel targets of miR-193a. MiR-193a mediated downregulation of MAX could suppress MYC activity since it is an obligate hetero-dimerization partner of MYC. MYC induced expression of miR-193a, therefore, seems to act as a feedback inhibitor of MYC signaling. The expression of miR-193a resulted in widespread repression of gene expression that included not only several cell cycle regulators, WNT, NOTCH signaling genes, and those encoding DNA replication machinery, but also several chromatin modifiers like SWI/SNF family genes and histone-encoding genes. MiR-193a expression brought about a reduction in the global levels of H3K4me3, H3K27ac, the histone marks of active chromatin, and an increase in the levels of H3K27me3, a repressive chromatin mark. In cancer cells having high MYC expression, MYC brings about transcriptional amplification of all active genes apart from the induction of its target genes. MiR-193a, on the other hand, brought about global repression of gene expression. Therefore, miR-193a has therapeutic potential in the treatment of not only Group 3 medulloblastomas but possibly other MYC overexpressing aggressive cancers as well.

Highlights

Medulloblastoma is the single most common malignant brain tumor in children [1]
MYC driven upregulation of promoter activity and expression levels of miR-193a, a WNT subgroup-specific microRNA We have earlier reported the differential expression of several microRNAs in the four molecular subgroups of medulloblastomas [10]
In order to delineate the molecular basis of the WNT subgroup-specific miR-193a expression, the miR-193a promoter region was analyzed for the binding sites of the WNT signaling target transcription factors

Summary

Introduction

Medulloblastoma is the single most common malignant brain tumor in children [1]. Standard treatment of medulloblastoma includes surgery, followed by craniospinal radiation and chemotherapy. The treatment results in the long-term survival of about 70% of average-risk patients. Three studies based on the integrated genomic analysis have identified multiple subtypes within Group 3/Group 4 subgroups, which are enriched in specific driver genetic alterations and copy number variations [3,4,5]. A meta-analysis of the three studies identified eight subtypes with some subtypes consisting of both Group 3 and Group 4 tumors, indicating a broad continuum of the subtypes [6]. Subtypes II, III, and V have the worst five-year overall survival and often carry amplification in the MYC and MYC/ MYCN gene, respectively

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Discussion

Conclusion