Abstract 4996: The m6A hallmark of cancer: RNA demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation

Abstract

Abstract N6-methyladenosine (m6A) is the most prevalent internal modification on mRNA, but its functions in human diseases are poorly understood. The dynamic and reversible m6A modification installed and erased by N6-methyltransferases and demethylases regulates cell fate and gene expression. We show that the m6A demethylase ALKBH5 is highly expressed in patient-derived glioblastoma stem-like cells (GSCs) and informs poor survival of patients with glioblastoma. Silencing ALKBH5 suppresses the proliferation of GSCs in vitro and in vivo. Results of integrated transcriptome and m6A-seq analyses reveal a global change of gene expression enriched in cell cycle and altered expression of select ALKBH5 targets. Among these targets, Ingenuity’s upstream regulator analysis identified FOXM1, an essential transcription factor for GSC proliferation, as a key mediator responsible for the disrupted proliferation program. Using multiple molecular and biochemical approaches, we demonstrate that ALKBH5 binds to and demethylates FOXM1 nascent transcripts. This promotes the interaction of FOXM1 pre-mRNA with HuR, thereby maintaining FOXM1 expression. Further, a long noncoding RNA antisense to the FOXM1 (FOXM1-AS) interacts with ALKBH5 as well as FOXM1 pre-mRNA and promotes their interaction. Depleting ALKBH5 and FOXM1-AS abolishes GSC tumorigenesis through the FOXM1 axis. The vulnerability of GSCs to disruptions in ALKBH5-dependent gene expression suggests that m6A has a central role in tumor development and provides a rationale for therapeutically targeting epitranscriptomic modulators in patients with glioblastoma. Citation Format: Sicong Zhang, Aidong Zhou, Oliver Bogler, Sadhan Majumder, Suyun Huang. The m6A hallmark of cancer: RNA demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4996. doi:10.1158/1538-7445.AM2017-4996