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

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

Cell Reports (May 2024)

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

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

Monica Pomaville: Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL 60637, USA
Mohansrinivas Chennakesavalu: Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL 60637, USA
Pingluan Wang: Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
Zhiwei Jiang: Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
Hui-Lung Sun: Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
Peizhe Ren: Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
Ryan Borchert: Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL 60637, USA
Varsha Gupta: Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL 60637, USA
Chang Ye: Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
Ruiqi Ge: Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
Zhongyu Zhu: Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
Mallory Brodnik: Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL 60637, USA
Yuhao Zhong: Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
Kelley Moore: Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL 60637, USA
Helen Salwen: Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL 60637, USA
Rani E. George: Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Malgorzata Krajewska: School of Biochemistry and Cell Biology, Biosciences Institute, University College Cork, Cork, Ireland
Alexandre Chlenski: Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL 60637, USA
Mark A. Applebaum: Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL 60637, USA
Chuan He: Department of Chemistry, University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, Il 60637 USA
Susan L. Cohn: Department of Pediatrics, University of Chicago Comer Children’s Hospital, Chicago, IL 60637, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 5
p. 114165

Abstract

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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.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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