학술논문
Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation
Document Type
article
Author
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
Source
Cell Reports, Vol 43, Iss 5, Pp 114165- (2024)
Subject
Language
English
ISSN
2211-1247
Abstract
Summary: The N6-methyladenosine (m6A) RNA modification is an important regulator of gene expression. m6A 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 m6A 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 m6A 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.