Nuclear NAD+ synthase nicotinamide mononucleotide adenylyltransferase 1 contributes to nuclear atypia and promotes glioma growth.

Background: Glioma is a malignant primary brain tumor with a poor prognosis and short survival. NAD⁺ is critical for cancer growth; however, clinical trials targeting NAD⁺ biosynthesis had limited success, indicating the need for mechanistic characterization. Nuclear atypia, aberrations in the size and shape of the nucleus, is widely observed in cancer and is often considered a distinctive feature in diagnosis; however, the molecular underpinnings are unclear.

Methods: We carried out high-resolution immunohistochemical analyses on glioma tissue samples from 19 patients to analyze the expression of NAD⁺ synthase nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), and its correlation with nuclear atypia in gliomas. Utilizing a Drosophila model of glial neoplasia, we investigated the genetic role of nuclear NMNAT in glioma growth in vivo, elucidating the cellular mechanisms of NMNAT1 in promoting nuclear atypia and glioma growth.

Results: In low-grade glioma and glioblastoma, a higher transcription level of NMNAT1 is correlated with poorer disease-free survival. Samples of high-grade gliomas contained a higher percentage of glial cells enriched with NMNAT1 protein. We identified a specific correlation between nuclear NMNAT1 protein level with nuclear atypia. Mechanistic studies in human glioma cell lines and in vivo Drosophila model suggest that NMNAT1 disrupts the integrity of the nuclear lamina by altering the distribution of lamin A/C and promotes glioma growth.

Conclusions: Our study uncovers a novel functional connection between the NAD⁺ metabolic pathway and glioma growth, reveals the contribution of the NAD⁺ biosynthetic enzyme NMNAT1 to nuclear atypia, and underscores the role of nuclear NMNAT1 in exacerbating glioma pathology.