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Direct Regulation of Alternative Splicing by SMAD3 through PCBP1 Is Essential to the Tumor-Promoting Role of TGF-β

Veenu Tripathi1, Katherine M Sixt1, Shaojian Gao2

  • 1Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Molecular Cell
|October 18, 2016
PubMed

Insights

Transforming growth factor-beta (TGF-β) switches from inhibiting to promoting cancer by altering CD44 splicing via SMAD3 and PCBP1 interaction. This mechanism is crucial for tumor progression and metastasis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Transforming growth factor-beta (TGF-β) paradoxically promotes tumor progression in advanced cancers, despite its inhibitory role in early stages.
  • The mechanisms by which TGF-β cooperates with receptor tyrosine kinase pathways to drive tumor growth remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying TGF-β's switch from a tumor suppressor to a tumor promoter.
  • To investigate the role of alternative splicing in TGF-β-mediated cancer progression.

Main Methods:

  • Investigated the interaction between SMAD3 and PCBP1 in response to TGF-β and EGF signaling.
  • Analyzed the alternative splicing of CD44 pre-mRNA in nuclear speckles.
  • Utilized cell-based assays to assess the functional impact of SMAD3-mediated splicing on cancer progression.

Main Results:

  • TGF-β directly regulates CD44 alternative splicing through a phosphorylated SMAD3-mediated interaction with PCBP1.
  • TGF-β and EGF signaling induce SMAD3 and PCBP1 to colocalize in nuclear speckles, where they interact with CD44 pre-mRNA.
  • This interaction inhibits spliceosome assembly, favoring the mesenchymal CD44s isoform over the epithelial CD44E isoform.
  • SMAD3-mediated alternative splicing is essential for TGF-β's tumor-promoting functions and influences epithelial-to-mesenchymal transition and metastasis.

Conclusions:

  • TGF-β promotes cancer progression by directly altering CD44 alternative splicing via the SMAD3-PCBP1 complex.
  • This splicing switch is a critical mechanism for TGF-β to promote epithelial-to-mesenchymal transition and metastasis.
  • Targeting this pathway could offer novel therapeutic strategies for advanced cancers.
Keywords:
CD44EMTPCBP1SMAD3TGF-βalternative splicingmetastasis

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