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Functional Interaction Between the Oncogenic Kinase NEK2 and Sam68 Promotes a Splicing Program Involved in Migration

Chiara Naro1,2, Federica Barbagallo3, Cinzia Caggiano1,2

  • 1Department of Neuroscience, Section of Human Anatomy, University of the Sacred Hearth, Rome, Italy.

Frontiers in Oncology
|May 9, 2022
PubMed

Insights

The oncogenic kinase NEK2 and RNA-binding protein Sam68 cooperate in triple-negative breast cancer (TNBC) to promote cell migration and invasion. Targeting this NEK2-Sam68 interaction could offer new therapeutic strategies for aggressive TNBC.

Area of Science:

  • Molecular Oncology
  • Cancer Biology
  • RNA Biology

Background:

  • Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis due to limited targeted therapies.
  • Dysregulated alternative splicing is a hallmark of TNBC, presenting potential therapeutic vulnerabilities.
  • The oncogenic kinase NEK2 is upregulated in TNBC and influences its splicing profile.

Purpose of the Study:

  • To investigate the molecular mechanisms of alternative splicing regulation in TNBC.
  • To elucidate the role of NEK2 and its interaction with RNA-binding proteins in TNBC progression.
  • To identify potential therapeutic targets by understanding the NEK2-Sam68 axis in TNBC metastasis.

Main Methods:

  • Investigated the interaction between NEK2 and Sam68 in TNBC cells.
  • Assessed NEK2-mediated phosphorylation of Sam68 and its impact on splicing activity.
  • Performed genome-wide transcriptome analysis to identify Sam68 splicing targets in TNBC.
  • Utilized gene depletion and kinase inhibition to evaluate functional effects on cell migration and invasion.

Main Results:

  • NEK2 interacts with and enhances the splicing activity of Sam68 in TNBC cells.
  • NEK2 and Sam68 co-regulate a common set of exons involved in cell migration and spreading.
  • Depletion of Sam68 reduces TNBC cell migration and invasion, an effect amplified by NEK2 inhibition.
  • Identified a functional cooperation between Sam68 and NEK2 in sustaining pro-metastatic features of TNBC.

Conclusions:

  • NEK2 and Sam68 form a functional axis that drives alternative splicing programs in TNBC.
  • This NEK2-Sam68-mediated splicing program promotes TNBC cell migration and invasion.
  • Targeting the NEK2-Sam68 interaction represents a promising therapeutic strategy for aggressive TNBC.
Keywords:
NEK2SAM68alternative splicingtranscriptomicstriple-negative breast cancer

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