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.

EMBO Reports
|January 11, 2021
PubMed

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.

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.1K
Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
4.9K
MicroRNAs01:22

MicroRNAs

MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
3.4K
MicroRNAs01:22

MicroRNAs

MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After...
23.2K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.9K
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
3.4K