Editors' ChoiceCancer

Noncanonical DNA modification revealed in glioblastoma

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Science Translational Medicine  21 Nov 2018:
Vol. 10, Issue 468, eaav9145
DOI: 10.1126/scitranslmed.aav9145


ALKBH1 promotes glioblastoma by controlling the N6-methyladenine DNA modification on hypoxia response genes.

Aberrant DNA methylation is one genetic driver of cancer. N6-methyladenine (6mA) is a noncanonical methylation on adenine that has been widely reported in prokaryotes as involved in the host defense system. However, its potential role in cancer has not been elucidated.

Using glioblastoma as a model system of human cancer, Xie et al. found that 6mA was up-regulated in glioblastoma cancer stem cells and primary glioblastoma patient tumors via several complementary approaches, including dot blots, mass spectrometry, and immunohistochemistry staining. Genomic profiling of 6mA revealed that this modification mainly occupied genes involved in neurogenesis and neuronal development. Further analyses suggested that 6mA was involved in repressive epigenetic regulation, as it was highly associated with the H3K9me3 histone modification.

The 6mA methyltransferase (such as N6AMT1) is known to promote 6mA modification, whereas the demethylase ALKBH1 removes the 6mA modification. The specific 6mA methyltransferases involved in glioblastoma remain unclear. This study focused on characterizing the function of ALKBH1 in this cancer. The authors found that ALKBH1 depletion led to decreased gene expression of hypoxia response pathways by modulating 6mA-dependent heterochromatin formation. Consequently, ALKBH1 depletion resulted in decreased glioblastoma stem cell self-renewal potential in vitro and prolonged tumor-bearing mice survival in vivo. Lastly, ALKBH1 expression and its positively regulated gene signature were associated with increased tumor grade and decreased survival in patients.

Overall, this study unveils a role of ALKBH1 and 6mA in cancer and shows that ALKBH1 may be a therapeutic target in glioblastoma. This study will hopefully motivate the development of ALKBH1 inhibitors in cancer. There are, however, remaining questions that need to be addressed. First and foremost, it will be important to identify the critical methyltransferase that promotes 6mA in glioblastoma. ALKBH1 is an enzyme that removes 6mA, and it is intriguing that both 6mA and ALKBH1 are up-regulated in glioblastoma, suggesting the complexity of this signaling axis in cancer. Also, the underlying mechanism by which ALKBH1 preferentially affects hypoxia responsive genes requires further investigation.

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