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PRMT5 as a Potential Therapeutic Target in MYC-Amplified Medulloblastoma.

ABSTRACT: MYC amplification or overexpression is most common in Group 3 medulloblastomas and is positively associated with poor clinical outcomes. Recently, protein arginine methyltransferase 5 (PRMT5) overexpression has been shown to be associated with tumorigenic MYC functions in cancers, particularly in brain cancers such as glioblastoma and medulloblastoma. PRMT5 regulates oncogenes, including MYC, that are often deregulated in medulloblastomas. However, the role of PRMT5-mediated post-translational modification in the stabilization of these oncoproteins remains poorly understood. The potential impact of PRMT5 inhibition on MYC makes it an attractive target in various cancers. PRMT5 inhibitors are a promising class of anti-cancer drugs demonstrating preclinical and preliminary clinical efficacies. Here, we review the publicly available preclinical and clinical studies on PRMT5 targeting using small molecule inhibitors and discuss the prospects of using them in medulloblastoma therapy.

SUBMITTER: Kumar D

PROVIDER: S-EPMC10741595 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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PRMT5 as a Potential Therapeutic Target in MYC-Amplified Medulloblastoma.

Kumar Devendra D Jain Stuti S Coulter Don W DW Joshi Shantaram S SS Chaturvedi Nagendra K NK

Cancers 20231215 24

MYC amplification or overexpression is most common in Group 3 medulloblastomas and is positively associated with poor clinical outcomes. Recently, protein arginine methyltransferase 5 (PRMT5) overexpression has been shown to be associated with tumorigenic MYC functions in cancers, particularly in brain cancers such as glioblastoma and medulloblastoma. PRMT5 regulates oncogenes, including MYC, that are often deregulated in medulloblastomas. However, the role of PRMT5-mediated post-translational m ...[more]

PMID: 38136401

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BET bromodomain inhibition of MYC-amplified medulloblastoma.

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Inhibition of enhancer of zest homologue 2 is a potential therapeutic target for high-MYC medulloblastoma.

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| S-EPMC3974267 | biostudies-literature

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| S-EPMC9529814 | biostudies-literature

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| S-EPMC4382927 | biostudies-literature

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| S-EPMC7906057 | biostudies-literature

Combined functional genomic and chemical screens identify SETD8 as a therapeutic target in MYC-driven medulloblastoma.

Project description:Medulloblastoma (MB) is the most prevalent malignant brain tumor in children, accounting for 20% of all childhood brain tumors. The molecular profiling of MB into 4 major subgroups (WNT, SHH, Grp3, and Grp4) emphasizes the heterogeneity of MB and opens paths in which treatments may be targeted to molecularly aggressive and distinct tumors. Current therapeutic strategies for Group 3 MB are challenging and can be accompanied by long-term side effects from treatment. The involvement of altered epigenetic machinery in neoplastic transformation in MB has become more evident. Thus, we performed an epigenomic RNAi and chemical screen and identified SETD8/PRE-SET7/KMT5a as a critical player in maintaining proliferation and cell survival of MB cells. We have found that inhibition of SETD8 effects the migration/invasive ability of MB cells. SETD8 alters H4K20me chromatin occupancy at key genes involved in tumor invasiveness and pluripotency. Interestingly, these results link the aggressive and metastatic behavior of MYC-driven MB with SETD8 activity. Based on our results, we suggest that SETD8 has a critical role mediating Group 3 MB tumorigenesis. Establishing a role for SETD8 as a factor in MYC-driven MB has potential to lead to more effective therapies needed to improve outcomes in high-risk patients.

| S-EPMC6485357 | biostudies-literature

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| S-EPMC5288228 | biostudies-literature

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