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

doi:10.1016/j.celrep.2024.114165

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

School of Biochemistry and Cell Biology

The University of Chicago
Dana-Farber Cancer Institute

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	114165
Journal	Cell Reports
Volume	43
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2024.114165
Publication status	Published - 28 May 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CP: Cancer
differentiation
epitranscriptome
gene expression regulation
mA
neuroblastoma
therapeutic target
tumor growth

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10.1016/j.celrep.2024.114165

Cite this

Pomaville, M., Chennakesavalu, M., Wang, P., Jiang, Z., Sun, H. L., Ren, P., Borchert, R., Gupta, V., Ye, C., Ge, R., Zhu, Z., Brodnik, M., Zhong, Y., Moore, K., Salwen, H., George, R. E., Krajewska, M., Chlenski, A., Applebaum, M. A., ... Cohn, S. L. (2024). Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation. Cell Reports, 43(5), Article 114165. https://doi.org/10.1016/j.celrep.2024.114165

@article{efbd207d72504190af5cb4499efe0777,

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

abstract = "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.",

keywords = "CP: Cancer, differentiation, epitranscriptome, gene expression regulation, mA, neuroblastoma, therapeutic target, tumor growth",

author = "Monica Pomaville and Mohansrinivas Chennakesavalu and Pingluan Wang and Zhiwei Jiang and Sun, \{Hui Lung\} and Peizhe Ren and Ryan Borchert and Varsha Gupta and Chang Ye and Ruiqi Ge and Zhongyu Zhu and Mallory Brodnik and Yuhao Zhong and Kelley Moore and Helen Salwen and George, \{Rani E.\} and Malgorzata Krajewska and Alexandre Chlenski and Applebaum, \{Mark A.\} and Chuan He and Cohn, \{Susan L.\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = may,

day = "28",

doi = "10.1016/j.celrep.2024.114165",

language = "English",

volume = "43",

journal = "Cell Reports",

issn = "2639-1856",

publisher = "Elsevier B.V.",

number = "5",

}

Pomaville, M, Chennakesavalu, M, Wang, P, Jiang, Z, Sun, HL, Ren, P, Borchert, R, Gupta, V, Ye, C, Ge, R, Zhu, Z, Brodnik, M, Zhong, Y, Moore, K, Salwen, H, George, RE, Krajewska, M, Chlenski, A, Applebaum, MA, He, C & Cohn, SL 2024, 'Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation', Cell Reports, vol. 43, no. 5, 114165. https://doi.org/10.1016/j.celrep.2024.114165

TY - JOUR

T1 - Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation

AU - Pomaville, Monica

AU - Chennakesavalu, Mohansrinivas

AU - Wang, Pingluan

AU - Jiang, Zhiwei

AU - Sun, Hui Lung

AU - Ren, Peizhe

AU - Borchert, Ryan

AU - Gupta, Varsha

AU - Ye, Chang

AU - Ge, Ruiqi

AU - Zhu, Zhongyu

AU - Brodnik, Mallory

AU - Zhong, Yuhao

AU - Moore, Kelley

AU - Salwen, Helen

AU - George, Rani E.

AU - Krajewska, Malgorzata

AU - Chlenski, Alexandre

AU - Applebaum, Mark A.

AU - He, Chuan

AU - Cohn, Susan L.

PY - 2024/5/28

Y1 - 2024/5/28

N2 - 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.

AB - 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.

KW - CP: Cancer

KW - differentiation

KW - epitranscriptome

KW - gene expression regulation

KW - mA

KW - neuroblastoma

KW - therapeutic target

KW - tumor growth

UR - https://www.scopus.com/pages/publications/85191861502

U2 - 10.1016/j.celrep.2024.114165

DO - 10.1016/j.celrep.2024.114165

M3 - Article

C2 - 38691450

AN - SCOPUS:85191861502

SN - 2639-1856

VL - 43

JO - Cell Reports

JF - Cell Reports

IS - 5

M1 - 114165

ER -

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

Abstract

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Keywords

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Drug targeting RNA modifications shows promise for treating neuroblastoma

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

Abstract

UN SDGs

Keywords

Access to Document

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Drug targeting RNA modifications shows promise for treating neuroblastoma

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