ALKBH1 Promotes N⁶-methyladenine DNA Modifications in Glioblastoma

N⁶-methyladenosine (N⁶-mA) methylation is a type of DNA modification that is prevalent in prokaryotic, but not eukaryotic, genomes. To elucidate the role of N⁶-mA DNA modifications in brain cancer, Xie, Wu, Gimple, and colleagues evaluated human patient–derived glioblastoma (GBM) stem cell (GSC) cultures for the presence of N⁶-mA DNA methylation. Compared to normal human astrocytes and brain tissue, GSC cultures and GBM exhibited high levels of N⁶-mA DNA modifications. Genomic profiling of N⁶-mA DNA modifications in GSCs and a primary GBM revealed that N⁶-mA DNA modifications were enriched in regions containing genes related to neurogenesis and neuronal development, and combined chromatin immunoprecipitation and sequencing (ChIP-seq) showed that N⁶-mA marks were enriched in heterochromatin-associated histone modification H3K9me3 domains in GSCs. ALKBH1 was shown to regulate N⁶-mA DNA demethylation in GSCs; further, knockdown of ALKBH1 in GSCs increased N⁶-mA DNA methylation levels and decreased the number of genomic loci exhibiting chromatin accessibility, and ChIP-seq revealed that ALKBH1 binds to regions enriched for N⁶-mA marks. Consistent with these findings, N⁶-mA sites that were induced by ALKBH1 depletion were highly correlated with heterochromatin histone modifications, and pathway analysis showed that loss of ALKBH1 resulted in the enrichment of oncogenic pathways such as hypoxia response, suggesting that ALKBH1 regulates gene expression by inhibiting N⁶-mA–dependent heterochromatin formation. ALKBH1 levels were increased in patient GBM and associated with decreased survival, and knockdown of ALKBH1 resulted in decreased GSC growth in vitro and in vivo. These results elucidate the role of N⁶-mA DNA modification in glioblastoma tumorigenesis and suggest that inhibition of ALKBH1 may be a therapeutic strategy for patients with GBM.

Xie Q, Wu TP, Gimple RC, Li Z, Prager BC, Wu Q, et al. N⁶A-methyladenine DNA modification in glioblastoma. Cell 2018 Nov 1 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.