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Published on: June 15, 2017
Phorbol ester enhances KAI1 transcription by recruiting Tip60/Pontin complexes
Alexandra Rowe1, Jörg Weiske, Tobias S Kramer
1Oncology Research Centre, Prince of Wales Hospital, Randwick, NSW, Australia.
Neoplasia (New York, N.Y.)
|December 3, 2008
Summary
Phorbol 12-myristate 13-acetate (PMA) up-regulates the KAI1 (CD82) metastasis suppressor in prostate cancer cells. This involves protein kinase C activation, histone acetylation, and Tip60/Pontin recruitment to the KAI1 promoter.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Down-regulation of the KAI1 (CD82) metastasis suppressor is observed in advanced human cancers.
- Mechanisms controlling KAI1 expression are crucial for understanding cancer progression.
- Previous studies implicated beta-catenin/Reptin complexes in suppressing KAI1 transcription.
Purpose of the Study:
- To investigate the pathway by which phorbol 12-myristate 13-acetate (PMA) increases KAI1 transcription in LNCaP prostate cancer cells.
- To elucidate the role of protein kinase C (PKC) and downstream signaling in PMA-induced KAI1 expression.
- To examine the epigenetic modifications and protein complex recruitment involved in KAI1 transcriptional regulation.
Main Methods:
- Utilized specific kinase inhibitors to dissect the signaling pathway (PKC, Ras, Raf, MEK, ERK, p38MAPK).
- Assessed histone acetylation (H3, H4) and protein expression levels.
- Employed chromatin immunoprecipitation (ChIP) to analyze the recruitment of activator complexes (Tip60/Pontin) to the KAI1 promoter.
- Investigated the subcellular localization of key proteins (Tip60).
Main Results:
- PMA-induced KAI1 transcription activation is mediated by classic PKC isoforms, MEK1/2, and ERK1/2, independent of Ras/Raf and p38MAPK.
- PMA treatment enhanced histone H3 and H4 acetylation, with H3 acetylation dependent on PKC.
- Chromatin immunoprecipitation confirmed PMA-induced recruitment of Tip60/Pontin complexes to NFkappaB-p50 motifs in the KAI1 promoter, a process inhibited by PKC inhibitors.
- PMA induced nuclear translocation of Tip60, without altering overall protein levels of Tip60, Pontin, beta-catenin, or Reptin.
Conclusions:
- PMA activates KAI1 transcription in prostate cancer cells via a PKC-dependent pathway involving MEK/ERK signaling.
- Epigenetic modifications, specifically histone H3 acetylation, and the recruitment of Tip60/Pontin complexes to the KAI1 promoter are critical for PMA-induced KAI1 expression.
- PMA-mediated nuclear translocation of Tip60 is a key event in overcoming KAI1 transcriptional repression.
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