Abstract 2545: NNMT is a novel effector of EGFR driven glioblastoma malignancy

Abstract

Abstract Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the conversion of methyl groups from S-adenosyl-L-methionine (SAM) to nicotinamide (NAM) to generate S-adenosine hyperblastoids (SAH) and 1-methylnicotinamide (MNA). Upregulation of NNMT has been observed in a variety of cancers, including glioblastoma. The mechanism by which NNMT is overexpressed in glioblastoma remains largely unknown. Epidermal growth factor receptor (EGFR) gene amplification or mutation is one of the most common genetic lesions in glioblastoma, and EGFRvIII is the most common mutant contributing to glioblastoma cell proliferation, invasion, therapeutic resistance, metastasis, and stemness. In this study, we show that activation of wild-type EGFR by EGF or the constitutively active mutant EGFRvIII promoted NNMT expression in established glioblastoma cell lines and glioblastoma stem-like cells via the p38 mitogen-activated protein kinase pathway. Furthermore, we identified STAT1 as a downstream transcription factor required for EGFR/EGFRvIII-induced NNMT upregulation. Knockdown of NNMT by RNA interference in glioblastoma cells significantly inhibited EGFRvIII-promoted glioblastoma cell invasion and proliferation in vitro. Targeting NNMT inhibited EGFRvIII-driven glioblastoma tumorigenicity and prolonged survival of tumor-bearing mice. Clinically, NNMT was highly expressed and positively correlated with EGFR expression in human glioblastoma tumors. Taken together, these findings establish NNMT as a previously unknown downstream target gene of EGFR/EGFRvIII expression and nominate it as a new potential therapeutic target for inhibiting EGFRvIII-driven glioblastoma. Citation Format: Lianping Ma, Ming Li. NNMT is a novel effector of EGFR driven glioblastoma malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2545.