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Inhibition of PRMT5/MEP50 Arginine Methyltransferase Activity Causes Cancer Vulnerability in NDRG2low Adult T-Cell

Tomonaga Ichikawa1,2, Akira Suekane3, Shingo Nakahata1,4

  • 1Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, Miyazaki 889-1692, Japan.

International Journal of Molecular Sciences
|March 13, 2024
PubMed

Insights

Loss of the tumor suppressor N-myc downstream-regulated gene 2 (NDRG2) in adult T-cell leukaemia/lymphoma (ATL) promotes cancer by activating PRMT5. Inhibiting PRMT5 offers a targeted therapy for NDRG2-low ATL.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • N-myc downstream-regulated gene 2 (NDRG2) acts as a tumor suppressor frequently lost in various cancers, including adult T-cell leukaemia/lymphoma (ATL).
  • Downregulation of NDRG2 expression correlates with tumor progression, partly due to aberrant signaling molecule phosphorylation.
  • NDRG2 loss induces protein arginine methyltransferase 5 (PRMT5) nuclear-to-cytoplasmic translocation via PRMT5 phosphorylation at Serine 335.

Purpose of the Study:

  • To investigate the role of PRMT5 in NDRG2-low ATL and evaluate PRMT5 inhibition as a therapeutic strategy.
  • To determine if PRMT5 activity is a viable drug target in tumors with reduced NDRG2 expression.

Main Methods:

  • Assessed the impact of PRMT5 and methylsome protein 50 (MEP50) knockdown on cell proliferation in NDRG2-low ATL cells.
  • Evaluated the effect of PRMT5-specific inhibitors (CMP5, HLCL61) on NDRG2-low versus NDRG2-expressing cancer cells.
  • Analyzed changes in client protein stability (AKT, NEMO) and HSP90A chaperone activity.

Main Results:

  • NDRG2 downregulation led to cytoplasmic PRMT5, enhancing HSP90A activity and promoting tumor progression in ATL.
  • Knockdown of PRMT5/MEP50 suppressed proliferation in NDRG2-low ATL cells by degrading AKT and NEMO.
  • NDRG2-expressing cells showed no impairment in client protein stability upon PRMT5/MEP50 manipulation.
  • PRMT5 inhibitors demonstrated greater sensitivity in NDRG2-low cancer cells, leading to client protein degradation.

Conclusions:

  • The interplay between PRMT5/MEP50 and NDRG2 downregulation presents a novel cancer vulnerability.
  • Targeting PRMT5 activity is a feasible and effective therapeutic strategy for NDRG2-low ATL.
  • PRMT5 inhibition disrupts HSP90A methylation and induces client protein degradation, offering a promising avenue for cancer treatment.
Keywords:
ATLMEP50NDRG2PRMT5cancer vulnerability

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