An NAD(+)-dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

作者：Gujar Amit D; Le Son; Mao Diane D; Dadey David Y A; Turski Alice; Sasaki Yo; Aum Diane; Luo Jingqin; Dahiya Sonika; Yuan Liya; Rich Keith M; Milbrandt Jeffrey; Hallahan Dennis E; Yano Hiroko; Tran David D; Kim Albert H^*

来源：Proceedings of the National Academy of Sciences, 2016, 113(51): E8247-E8256.

DOI：10.1073/pnas.1610921114

• glioblastoma
• NAMPT
• NAD(+)
• self-renewal
• radiation resistance

Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD(+)). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD(+) synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD(+) levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD(+)-dependent network. Accordingly, we demonstrate E2F2 is required for GSC self-renewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD(+) metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.

• 出版日期2016-12-20