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

eLife

Yi Zhu¹  Zoraida Diaz-Perez¹  Xianzun Tao¹  Chong Li¹  Kai Ruan¹  R Grace Zhai²  Priyamvada Rai³  Hongbo Wang⁴  Jiaqi Liu⁵ 

[1] Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States;Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States;Sylvester Comprehensive Cancer Center, Miami, United States;Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, United States;Sylvester Comprehensive Cancer Center, Miami, United States;School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Shandong, China;School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Shandong, China;Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States;

关键词: RAS;    PARP;    NAD;    caspase;    glial cell;    deacetylation;    D. melanogaster;   

DOI  :  10.7554/eLife.70046

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY