Small-molecule Inhibition of the METTL3/METTL14 Complex Suppresses Neuroblastoma Tumor Growth and Promotes Differentiation

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2024 May 1

PMID 38691450

Authors

Monica Pomaville

Mohansrinivas Chennakesavalu

Pingluan Wang

Zhiwei Jiang

Hui-Lung Sun

Peizhe Ren

Ryan Borchert

Varsha Gupta

Chang Ye

Ruiqi Ge

Zhongyu Zhu

Mallory Brodnik

Yuhao Zhong

Kelley Moore

Helen Salwen

Rani E George

Malgorzata Krajewska

Alexandre Chlenski

Mark A Applebaum

Chuan He

Susan L Cohn

Affiliations

Soon will be listed here.

Abstract

The N-methyladenosine (mA) RNA modification is an important regulator of gene expression. mA is deposited by a methyltransferase complex that includes methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14). High levels of METTL3/METTL14 drive the growth of many types of adult cancer, and METTL3/METTL14 inhibitors are emerging as new anticancer agents. However, little is known about the mA epitranscriptome or the role of the METTL3/METTL14 complex in neuroblastoma, a common pediatric cancer. Here, we show that METTL3 knockdown or pharmacologic inhibition with the small molecule STM2457 leads to reduced neuroblastoma cell proliferation and increased differentiation. These changes in neuroblastoma phenotype are associated with decreased mA deposition on transcripts involved in nervous system development and neuronal differentiation, with increased stability of target mRNAs. In preclinical studies, STM2457 treatment suppresses the growth of neuroblastoma tumors in vivo. Together, these results support the potential of METTL3/METTL14 complex inhibition as a therapeutic strategy against neuroblastoma.

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