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Smad7 Enhances TGF-β-Induced Transcription of c-Jun and HDAC6 Promoting Invasion of Prostate Cancer Cells

Noopur Thakur1, Anahita Hamidi1,2, Jie Song3

  • 1Ludwig Institute for Cancer Research, Ltd., Science for Life Laboratory, Uppsala University, Box 595, 751 24 Uppsala, Sweden.

Iscience
|September 5, 2020
PubMed

Insights

Smad7, a protein induced by transforming growth factor beta (TGF-β), promotes prostate cancer metastasis by enhancing the expression of c-Jun and HDAC6. High levels of Smad7, HDAC6, and c-Jun correlate with poor patient prognosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Transforming growth factor beta (TGF-β) signaling is critical in cancer progression, promoting cell migration and invasion.
  • Smad7 acts as a negative feedback regulator of TGF-β signaling.
  • The role of Smad7 in prostate cancer progression beyond negative feedback is not fully understood.

Purpose of the Study:

  • To investigate the novel function of Smad7 in promoting prostate cancer cell migration and invasion.
  • To identify the molecular mechanisms by which Smad7 enhances TGF-β-induced gene expression.
  • To correlate the expression of Smad7, c-Jun, and HDAC6 with patient prognosis in prostate cancer.

Main Methods:

  • Silencing of endogenous Smad proteins using siRNA.
  • Analysis of Smad7 binding to regulatory regions of c-Jun and HDAC6.
  • Correlation analysis of gene expression in public prostate cancer tissue databases.
  • Prognostic analysis based on Smad7, HDAC6, and c-Jun expression levels.

Main Results:

  • Smad7 enhances TGF-β-induced transcription of c-Jun and HDAC6 by binding to their regulatory regions.
  • Lysine 102 of Smad7 is essential for this interaction, independent of Smad2, 3, and 4.
  • Positive correlations were observed between the mRNA expression of Smad7 and HDAC6, Smad7 and c-Jun, and c-Jun and HDAC6 in prostate cancer tissues.
  • High expression of Smad7, HDAC6, and c-Jun is associated with poor prognosis in prostate cancer patients.

Conclusions:

  • Smad7 possesses a pro-metastatic function in prostate cancer by promoting the transcription of proinvasive genes c-Jun and HDAC6.
  • Smad7's interaction with c-Jun and HDAC6 regulatory regions represents a novel mechanism driving prostate cancer progression.
  • The findings highlight Smad7, HDAC6, and c-Jun as potential therapeutic targets and prognostic biomarkers for prostate cancer.
Keywords:
CancerCell BiologyMolecular Biology

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