NMNAT promotes glioma growth through regulating post-translational modifications of P53 to inhibit apoptosis.

Jiaqi Liu,R Grace Zhai,Hongbo Wang,Kai Ruan,Chong Li,Priyamvada Rai,Zoraida Diaz-Perez,Yi Zhu,Xianzun Tao

doi:10.7554/elife.70046

Abstract

Gliomas are highly malignant brain tumors with poor prognosis and short survival. NAD+ has been shown to impact multiple processes that are dysregulated in cancer; however, anti-cancer therapies targeting NAD+ synthesis have had limited success due to insufficient mechanistic understanding. Here, we adapted a Drosophila glial neoplasia model and discovered the genetic requirement for NAD+ synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) in glioma progression in vivo and in human glioma cells. Overexpressing enzymatically active NMNAT significantly promotes glial neoplasia growth and reduces animal viability. Mechanistic analysis suggests that NMNAT interferes with DNA damage-p53-caspase-3 apoptosis signaling pathway by enhancing NAD+-dependent posttranslational modifications (PTMs) poly(ADP-ribosyl)ation (PARylation) and deacetylation of p53. Since PARylation and deacetylation reduce p53 pro-apoptotic activity, modulating p53 PTMs could be a key mechanism by which NMNAT promotes glioma growth. Our findings reveal a novel tumorigenic mechanism involving protein complex formation of p53 with NAD+ synthetic enzyme NMNAT and NAD+-dependent PTM enzymes that regulates glioma growth.

Highlights

Glioma is the most common intrinsic tumor of the central nervous system (CNS) and derives from the neoplastic glial cells or neuroglia (Goodenberger and Jenkins, 2012)
When Rasv12 was expressed in glia, numerous glial neoplasia tissues marked by Green fluorescent protein (GFP) and Repo in the brain and ventral nerve cord (VNC) were detected as early as 100 hr after egg laying (AEL), and the volumes of glial neoplasia increased with age (Figure 1A, B and G)
Since NAD+ plays important regulatory roles in both DNA damage repair and cell apoptosis, and NAD+ synthase activity is required for glial neoplasia growth (Figure 2), we examined the effect of nicotinamide mononucleotide adenylyltransferase (NMNAT) on the DNA damage pathway in glioma

Summary

Introduction

Glioma is the most common intrinsic tumor of the central nervous system (CNS) and derives from the neoplastic glial cells or neuroglia (Goodenberger and Jenkins, 2012). Cancer Biology | Neuroscience eLife digest One of the most common types of brain cancer, glioma, emerges when harmful mutations take place in the ‘glial’ cells tasked with supporting neurons. When these genetically damaged cells are not fixed or eliminated, they can go on to multiply uncontrollability. A protein known as p53 can help to repress emerging tumors by stopping mutated cells in their tracks

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