SMCX/JARID1C was recently shown to be a historic H3 lysine 4 (H3K4) demethylase. Here, we have identified an SMCX isoform that predominantly resides in the cytoplasm, but still efficiently demethylates trimethylated H3K4. SMCX requires several functional domains for its demethylase activity and is also capable of forming homomers through amino acids 204-493. Further, SMCX physically interacts with Smad3, a mediator of transforming growth factor-beta (TGF-beta), and overexpression of SMCX inhibits the ability of Smad3 to activate transcription. Thus, SMCX is a novel Smad3 corepressor that may antagonize the tumor suppressing activity of the TGF-beta/ Smad3 signaling pathway and thereby contribute to tumorigenesis. Indeed, SMCX is overexpressed in prostate tumors and seminomas, suggesting that SMCX might be a novel oncogene. (c) 2007 Elsevier Inc. All rights reserved.