SET8 is a novel negative regulator of TGF-ß signaling in a methylation-independent manner.

ABSTRACT

Transforming growth factor ß (TGF-ß) is a multifunctional cytokine that induces a diverse set of cellular processes principally through Smad-dependent transcription. Transcriptional responses induced by Smads are tightly regulated by Smad cofactors and histone modifications; however, the underlying mechanisms have not yet been elucidated in detail. We herein report lysine methyltransferase SET8 as a negative regulator of TGF-ß signaling. SET8 physically associates with Smad2/3 and negatively affects transcriptional activation by TGF-ß in a catalytic activity-independent manner. The depletion of SET8 results in an increase in TGF-ß-induced plasminogen activator inhibitor-1 (PAI-1) and p21 expression and enhances the antiproliferative effects of TGF-ß. Mechanistically, SET8 occupies the PAI-1 and p21 promoters, and a treatment with TGF-ß triggers the replacement of the suppressive binding of SET8 with p300 on these promoters, possibly to promote gene transcription. Collectively, the present results reveal a novel role for SET8 in the negative regulation of TGF-ß signaling.