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

Abstract

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.

Schlafen 11 further sensitizes BRCA-deficient cells to PARP inhibitors through single-strand DNA gap accumulation behind replication forks

“…To examine the reciprocal effects of BRCA1/2 and SLFN11, we employed the SLFN11-expressing ovarian endometrioid adenocarcinoma TOV-112D and medulloblastoma DAOY cell lines in their SLFN11-knockout (SLFN11-KO) counterparts, which we recently shown to be hypersensitive to camptothecin (CPT) and cisplatin [32,33], Deleterious mutations in BRCA1 and BRCA2 are absent in either cell line according to the Cancer Cell Line Encyclopedia database (https://discover.nci.nih.gov/rsconnect/cellminercdb/) [39].…”

“…S8096) were obtained from Selleckchem. Generation of SLFN11-deleted cells SLFN11-knockout (KO) cells in DAOY were previously published [32] and SLFN11-KO cells in TOV-112D were generated in another study [33]. Disruption of the SLFN11 gene using the CRISPR/Cas9 method was reported previously [9].…”

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

“…Several efforts have been channeled towards targeting the different drivers that promote the development and maintenance of treatment resistance in medulloblastoma. In this context, Nakata et al showed that epigenetic targeting via the histone deacetylase (HDAC) inhibitor RG2833 in WNT and SHH medulloblastoma results in hypomethylation of the Schlafen11 gene and overproduction of SLFN11, which makes tumor cells vulnerable to cisplatin treatment as confirmed in rodent models [ 104 ]. Similarly, epigenetic regulation of MYC through pharmacological and genetic inactivation of the upstream Ableson tyrosine kinase (ABL1/2) results in decreased C-MYC expression and tumor progression.…”

Clinical impact of molecular profiling in rare brain tumors

“…These mutations offer the opportunity to develop clinical trials focused on specific subtypes of SHH-medulloblastoma across the age spectrum and explore the role of drugs targeting the spliceosome, synthetic lethality, or immunotherapy. Finally, other emerging markers of response to DNA damaging agents in solid tumors such as Schlafen family member 11 (SLFN11) have been shown to be differentially expressed across medulloblastoma subgroups, being more frequent in WNT and a proportion of SHH tumors and confer increasing sensitivity to cisplatin and topoisomerase inhibition in vivo and in vitro [59]. This may have implications for treatment selection in adults with medulloblastoma, for whom adjuvant chemotherapy has shown a survival benefit but is associated with significant toxicity.…”