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Published on: June 6, 2025
MYC promotes cancer progression by modulating m6 A modifications to suppress target gene translation
Gongwei Wu1,2, Caixia Suo1,3, Ying Yang4
1Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China.
Abstract:
The MYC oncoprotein activates and represses gene expression in a transcription-dependent or transcription-independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down-regulating N6-methyladenosine (m6 A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m6 A levels in the mRNA of the selected MRGs SPI1 and PHF12. We also show that MYC-regulated m6 A controls the translation of MRG mRNA via the specific m6 A reader YTHDF3. Finally, we find that inhibition of ALKBH5, or overexpression of SPI1 or PHF12, effectively suppresses the growth of MYC-deregulated B-cell lymphomas, both in vitro and in vivo. Our findings uncover a novel mechanism by which MYC suppresses gene expression by altering m6 A modifications in selected MRG transcripts promotes cancer progression.
Insights
MYC oncogene promotes cancer by reducing N6-methyladenosine (m6 A) mRNA modifications in key genes. Inhibiting ALKBH5 or overexpressing SPI1/PHF12 suppressed tumor growth, revealing a new therapeutic target.
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- The MYC oncoprotein is a key regulator of gene expression implicated in cancer progression.
- Messenger RNA (mRNA) modifications, such as N6-methyladenosine (m6 A), are critical for gene expression regulation.
- The interplay between MYC and mRNA modification in cancer remains incompletely understood.
Purpose of the Study:
- To investigate whether MYC alters mRNA modifications.
- To determine the role of MYC-mediated m6 A regulation in cancer progression.
- To explore potential therapeutic strategies targeting MYC-regulated mRNA modification pathways.
Main Methods:
- Analysis of MYC's effect on m6 A levels in MYC-repressed genes (MRGs).
- Investigated the role of ALKBH5, a demethylase, in MYC-mediated m6 A regulation.
- Examined the impact of m6 A reader YTHDF3 on MRG mRNA translation.
- Utilized in vitro and in vivo models of MYC-deregulated B-cell lymphomas to assess therapeutic interventions.
Main Results:
- MYC down-regulates m6 A levels in specific MYC-repressed genes (MRGs), including SPI1 and PHF12, promoting cancer.
- MYC increases ALKBH5 expression, contributing to reduced m6 A levels in target mRNAs.
- MYC-regulated m6 A modification controls the translation of MRG mRNAs via YTHDF3.
- Inhibition of ALKBH5 or overexpression of SPI1/PHF12 suppressed B-cell lymphoma growth.
Conclusions:
- MYC promotes cancer progression by epigenetically silencing gene expression through down-regulation of m6 A modification in specific MRGs.
- The MYC-ALKBH5-m6 A-YTHDF3 axis represents a novel mechanism of oncogene-driven cancer.
- Targeting ALKBH5 or key downstream effectors like SPI1/PHF12 holds therapeutic potential for MYC-driven cancers.
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