Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation

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 c...

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Published in:	Cell reports (Cambridge) Vol. 43; no. 5; p. 114165
Main Authors:	Pomaville, Monica, Chennakesavalu, Mohansrinivas, Wang, Pingluan, Jiang, Zhiwei, Sun, Hui-Lung, Ren, Peizhe, Borchert, Ryan, Gupta, Varsha, Ye, Chang, Ge, Ruiqi, Zhu, Zhongyu, Brodnik, Mallory, Zhong, Yuhao, Moore, Kelley, Salwen, Helen, George, Rani E., Krajewska, Malgorzata, Chlenski, Alexandre, Applebaum, Mark A., He, Chuan, Cohn, Susan L.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 28-05-2024 Elsevier
Subjects:	Adenosine - analogs & derivatives Adenosine - metabolism Adenosine - pharmacology Animals Cell Differentiation - drug effects Cell Line, Tumor Cell Proliferation - drug effects CP: Cancer differentiation epitranscriptome gene expression regulation Gene Expression Regulation, Neoplastic - drug effects Humans m6A Methyltransferases - antagonists & inhibitors Methyltransferases - metabolism Mice neuroblastoma Neuroblastoma - drug therapy Neuroblastoma - genetics Neuroblastoma - metabolism Neuroblastoma - pathology therapeutic target tumor growth gene expression regulation differentiation CP: Cancer neuroblastoma m6A tumor growth epitranscriptome therapeutic target mA
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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. [Display omitted] •Expression of RNA methyltransferases METTL3/14 correlates with survival in neuroblastoma•Inhibition of METTL3/14 decreases cell survival and reduces tumor growth in xenograft models•METTL3/14 inhibition regulates RNA stability by mediating site-specific m6A loss•METTL3/14 inhibition up-regulates differentiation-associated transcriptional networks Pomaville et al. show that the catalytic activity of the METTL3/14 complex is critical for neuroblastoma growth. Pharmacological inhibition of METTL3/14 promoted neuroblastoma differentiation and suppressed tumor xenograft growth. Inhibitor treatment mediated m6A loss at sites specific for neuronal differentiation, increasing transcript stability and the expression of neuronal differentiation networks.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Conceptualization, M.P., S.L.C., C.H., R.E.G., and M.K.; investigation, M.P., Z.J., P.W., M.C., H.-L.S., P.R., R.B., V.G., A.C., C.Y., R.G., Z.Z., M.B., Y.Z., K.M., and H.S.; writing – original draft, M.P. and S.L.C.; writing – review & editing, H.S., A.C., R.E.G., M.A.A., C.H., and S.L.C., visualization, M.P. and M.C.; supervision, M.A.A., C.H., and S.L.C.; funding acquisition, C.H. and S.L.C.
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2024.114165