Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin

Background: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma.

Methods: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo.

Results: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells.

Conclusions: High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.

 

Comments:

The provided background outlines a study focused on understanding the role of Schlafen family member 11 (SLFN11) in medulloblastoma, a type of brain tumor that predominantly affects children. The study investigates the expression and functions of SLFN11 in different molecular subgroups of medulloblastoma and its impact on patient survival.

### Key Findings:

1. **Identification of SLFN11 as a Prognostic Marker:**
   - SLFN11 was identified through unbiased screening as one of the top prognostic markers in medulloblastomas.
   - Higher expression of SLFN11 was associated with significantly longer survival in patients.

2. **Expression Across Molecular Subgroups:**
   - SLFN11 was found to be highly expressed in the WNT-activated subgroup and a subset of the SHH-activated subgroup.
   - WNT activation was not a direct cause of high SLFN11 expression, but a specific hypomethylation locus on the SLFN11 promoter was correlated with elevated expression.

3. **Genetic and Epigenetic Modulation of SLFN11:**
   - Modulation of SLFN11 expression in medulloblastoma cell lines revealed its impact on the response to DNA damaging agents.
   - Overexpression of SLFN11 increased sensitivity to cisplatin, while its deletion conferred resistance to the topoisomerase I inhibitor SN-38.

4. **Pharmacological Upregulation of SLFN11:**
   - The study explored the use of the brain-penetrant histone deacetylase inhibitor RG2833 to upregulate SLFN11 pharmacologically.
   - Treatment with RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells.

5. **In Vivo Studies:**
   - Intracranial xenograft studies supported the in vitro findings, showing marked sensitivity to cisplatin in SLFN11-overexpressing medulloblastoma cells.

### Conclusions: The study concludes that high SLFN11 expression is a favorable factor in WNT-activated and a subset of SHH-activated medulloblastomas. This favorable outcome is attributed to enhanced sensitivity to DNA damaging agents, specifically cisplatin. The findings suggest that SLFN11 could serve as a potential biomarker for prognosis and as a therapeutic target for improving outcomes in certain medulloblastoma subgroups. The use of histone deacetylase inhibitors to pharmacologically upregulate SLFN11 provides a promising avenue for future therapeutic interventions.

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HDAC