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CK2α' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation

Yuan Liu1, Elianna B Amin1, Marty W Mayo2

  • 1Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Cancer Research
|March 17, 2016
PubMed

Insights

Loss of breast cancer metastasis suppressor 1 (BRMS1) in lung cancer promotes metastasis. CK2α

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Breast cancer metastasis suppressor 1 (BRMS1) is downregulated in non-small cell lung cancer (NSCLC), correlating with increased metastasis.
  • The precise regulatory mechanisms controlling BRMS1 levels and its role in metastasis remain incompletely understood.

Purpose of the Study:

  • To elucidate the posttranslational regulation of BRMS1.
  • To investigate the role of BRMS1 regulation in NSCLC metastasis.
  • To identify potential therapeutic targets for inhibiting lung cancer metastasis.

Main Methods:

  • Investigated BRMS1 posttranslational modification using phosphorylation assays and Western blotting.
  • Utilized an in vivo orthotopic mouse model of lung cancer to assess metastasis.
  • Analyzed 160 human NSCLC specimens for expression levels of CK2α' and BRMS1.

Main Results:

  • Tumor necrosis factor (TNF)-induced phosphorylation of nuclear BRMS1 by casein kinase 2 catalytic subunit (CK2α') on serine 30 (S30) leads to nuclear export.
  • This process results in increased cytosolic BRMS1, subsequent degradation via the ubiquitin-proteasome pathway, and enhanced cell migration and invasion.
  • CK2α' inhibition or S30 mutation significantly reduced NSCLC metastasis in mice by 60-fold; high CK2α' and cytoplasmic BRMS1 correlated with poor patient outcomes.

Conclusions:

  • CK2α'-mediated phosphorylation and degradation of BRMS1 is a key mechanism promoting NSCLC metastasis.
  • Targeting this posttranslational modification pathway offers a potential therapeutic strategy to reduce lung cancer spread.
  • CK2α' and cytoplasmic BRMS1 levels serve as prognostic biomarkers for NSCLC recurrence and survival.

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