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PRMT5 activates AKT via methylation to promote tumor metastasis

Lei Huang1, Xiao-Ou Zhang2,3, Esteban J Rozen1

  • 1Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA, USA.

Nature Communications
|July 8, 2022
PubMed

Insights

Protein arginine methyltransferase 5 (PRMT5) inhibition blocks cancer growth and metastasis by preventing AKT activation. This finding suggests PRMT5 as a therapeutic target for high-risk metastatic cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Protein arginine methyltransferase 5 (PRMT5) is crucial for cellular processes and its dysregulation is linked to cancer.
  • PRMT5 catalyzes symmetric-dimethyl-arginine marks on various proteins, influencing cellular signaling pathways.

Purpose of the Study:

  • To investigate the role of PRMT5 in regulating protein kinase B (AKT) signaling.
  • To determine the impact of PRMT5 inhibition on cancer progression and metastasis.

Main Methods:

  • Utilized pharmacologic and genetic inhibition of PRMT5.
  • Assessed AKT methylation, translocation, and phosphorylation.
  • Examined the expression of epithelial-mesenchymal-transition (EMT) factors.
  • Evaluated tumor growth and metastasis in xenograft models.

Main Results:

  • PRMT5 directly methylates AKT, a prerequisite for its phosphorylation at Thr308 and Ser473.
  • PRMT5 inhibition prevents AKT1 methylation, plasma membrane translocation, and activation by PDK1 and mTOR2.
  • PRMT5/AKT signaling regulates expression of EMT transcription factors ZEB1, SNAIL, and TWIST1.
  • PRMT5 inhibition significantly reduced tumor growth and metastasis in neuroblastoma models.

Conclusions:

  • PRMT5-mediated AKT methylation is a critical step in oncogenic signaling.
  • Targeting PRMT5 offers a potential therapeutic strategy for high-risk metastatic cancers.
  • PRMT5 inhibition may enhance the efficacy of anti-AKT therapies.

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