Combined functional genomic and chemical screens identify SETD8 as a therapeutic target in MYC-driven medulloblastoma
Bethany Veo1, Etienne Danis1, Angela Pierce1,2
1Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Abstract:
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.
Insights
SETD8 is crucial for Group 3 medulloblastoma (MB) cell survival and invasion. Inhibiting SETD8 may offer a targeted therapy for this aggressive pediatric brain tumor.
Area of Science:
- Oncology
- Neuroscience
- Epigenetics
Background:
- Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with Group 3 MB posing significant therapeutic challenges.
- Altered epigenetic machinery is increasingly recognized in MB tumorigenesis, necessitating novel therapeutic targets.
Purpose of the Study:
- To identify key epigenetic regulators in medulloblastoma proliferation and survival.
- To investigate the role of SETD8 in Group 3 MB tumorigenesis and its potential as a therapeutic target.
Main Methods:
- Epigenomic RNAi and chemical screening were employed to identify critical genes in MB.
- SETD8 inhibition effects on MB cell proliferation, survival, and invasion were assessed.
- Chromatin occupancy of H4K20me at key genes was analyzed.
Main Results:
- SETD8 (also known as PRE-SET7/KMT5a) was identified as a critical factor for MB cell proliferation and survival.
- Inhibition of SETD8 significantly reduced MB cell migration and invasion.
- SETD8 modulates H4K20me chromatin occupancy at genes associated with tumor invasiveness and pluripotency.
- SETD8 activity is linked to the aggressive, metastatic behavior of MYC-driven MB.
Conclusions:
- SETD8 plays a critical role in Group 3 medulloblastoma tumorigenesis, particularly in MYC-driven tumors.
- Targeting SETD8 presents a promising therapeutic strategy to improve outcomes for high-risk MB patients.
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