Phorbol ester enhances KAI1 transcription by recruiting Tip60/Pontin complexes.
Down-regulation of the KAI1 (CD82) metastasis suppressor is common in advanced human cancer, but underlying mechanism(s) regulating KAI1 expression are only now being elucidated. Recent data provide evidence that low levels of KAI1 mRNA in LNCaP cells are caused by binding of beta-catenin/Reptin complexes to a specific motif in the proximal promoter, which prevents binding of Tip60/Pontin activator complexes to the same motif, thus inhibiting transcription. Here, we explored a pathway by which phorbol 12-myristate 13-acetate (PMA) up-regulates KAI1 transcription in LNCaP prostate cancer cells. Pretreatment with specific inhibitors showed that induction of KAI1 by PMA uses classic isoforms of protein kinase C (cPKC), is independent of Ras and Raf, and requires activation of MEK1/2 and ERK1/2, but does not involve p38MAPK. Induction of KAI1 transcription by PMA was associated with enhanced overall acetylation of histones H3 and H4, but only acetylation of H3 was blocked by a PKC inhibitor. Chromatin immunoprecipitation showed that PMA induces recruitment of Tip60/Pontin activator complexes to NFkappaB-p50 motifs in the proximal promoter, and this was blocked by a PKC inhibitor. These changes were not associated with differences in overall levels of Tip60, Pontin, beta-catenin, or Reptin protein expression but with PMA-induced nuclear translocation of Tip60.
Rowe
Alexandra
A
Oncology Research Centre, Prince of Wales Hospital, Randwick, NSW, Australia.
Weiske
Jörg
J
Kramer
Tobias S
TS
Huber
Otmar
O
Jackson
Paul
P
D000074183:ATPases Associated with Diverse Cellular Activities; D021581:Active Transport, Cell Nucleus; D002273:Carcinogens; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051861:Kangai-1 Protein / Q000096:biosynthesis*; D000074443:Lysine Acetyltransferase 5; D009362:Neoplasm Metastasis; D010703:Phorbol Esters / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002273:Carcinogens; D002352:Carrier Proteins; D006657:Histones; D051861:Kangai-1 Protein; D010703:Phorbol Esters; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D048051:p38 Mitogen-Activated Protein Kinases; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C486549:RUVBL1 protein, human; D013755:Tetradecanoylphorbol Acetate