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mTORC1 promotes cell growth via m6A-dependent mRNA degradation

Sungyun Cho1, Gina Lee2, Brian F Pickering1

  • 1Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA.

Molecular Cell
|March 23, 2021
PubMed

Insights

Dysregulated mTORC1 signaling promotes cancer by enhancing translation of WTAP, a key N6-methyladenosine (m6A) RNA modifier. This pathway, involving WTAP, MXD2, and cMyc, offers new therapeutic targets for mTORC1-driven cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • RNA Modification

Background:

  • Dysregulated mTORC1 signaling is implicated in metabolic disorders and cancer.
  • Understanding downstream effectors of mTORC1 is crucial for identifying therapeutic targets.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which mTORC1 signaling influences cancer progression.
  • To identify novel therapeutic targets within the mTORC1 signaling pathway.

Main Methods:

  • Investigated the role of mTORC1 and S6K in regulating translation of Wilms' tumor 1-associated protein (WTAP) mRNA.
  • Utilized single-nucleotide-resolution m6A mapping to analyze RNA modifications.
  • Examined the impact of WTAP on cMyc-MAX association and gene expression.

Main Results:

  • mTORC1 and S6K enhance eIF4A/4B-mediated translation of WTAP mRNA.
  • WTAP promotes cMyc-MAX association by suppressing MXD2 expression, thereby enhancing cMyc transcriptional activity.
  • m6A modification of MAX dimerization protein 2 (MXD2) mRNA promotes its degradation.

Conclusions:

  • mTORC1 signaling stimulates oncogenic pathways through m6A RNA modification.
  • The WTAP-MXD2-cMyc axis represents a potential therapeutic target for mTORC1-driven cancers.
Keywords:
MXD2Protein translationS6K1WTAPYTHDF readerscMyceIF4Am(6)A mRNA modificationmRNA stabilitymTORC1

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