Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma
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...
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-020-00942-5 |
| _version_ | 1818048906690297856 |
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| author | Harish Shrikrishna Bharambe Annada Joshi Kedar Yogi Sadaf Kazi Neelam Vishwanath Shirsat |
| author_facet | Harish Shrikrishna Bharambe Annada Joshi Kedar Yogi Sadaf Kazi Neelam Vishwanath Shirsat |
| author_sort | Harish Shrikrishna Bharambe |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T10:29:08Z |
| format | Article |
| id | doaj.art-9339b2cc474a4752abe50d3724e41a64 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-10T10:29:08Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-9339b2cc474a4752abe50d3724e41a642022-12-22T01:52:38ZengBMCActa Neuropathologica Communications2051-59602020-05-018111510.1186/s40478-020-00942-5Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastomaHarish Shrikrishna Bharambe0Annada Joshi1Kedar Yogi2Sadaf Kazi3Neelam Vishwanath Shirsat4Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, KhargharAdvanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, KhargharAdvanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, KhargharAdvanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, KhargharAdvanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, KhargharAbstract 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.http://link.springer.com/article/10.1186/s40478-020-00942-5MiR-193aMYCMAXMedulloblastomaPromoter methylation |
| spellingShingle | Harish Shrikrishna Bharambe Annada Joshi Kedar Yogi Sadaf Kazi Neelam Vishwanath Shirsat Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma Acta Neuropathologica Communications MiR-193a MYC MAX Medulloblastoma Promoter methylation |
| title | Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma |
| title_full | Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma |
| title_fullStr | Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma |
| title_full_unstemmed | Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma |
| title_short | Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma |
| title_sort | restoration of mir 193a expression is tumor suppressive in myc amplified group 3 medulloblastoma |
| topic | MiR-193a MYC MAX Medulloblastoma Promoter methylation |
| url | http://link.springer.com/article/10.1186/s40478-020-00942-5 |
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