Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-β1-mediated growth suppression in adult T-cell leukemia/lymphoma

Zinc-finger E-box binding homeobox 1 (ZEB1) is a candidate tumor-suppressor gene in adult T-cell leukemia/lymphoma ( ATLL). ZEB1 binds phosphorylated Smad2/3 to enhance transforming growth factor-beta 1 (TGF-beta 1) signaling. In addition to downregulation of ZEB1 mRNA, we found overexpression of inhibitory Smad, Smad7, in resistance of ATLL cells to growth suppression by TGF-beta 1. A protein complex of Smad7 and histone deacetylase constantly bound to the promoter region of TGF-beta 1 responsive genes with the Smad-responsive element (SRE) to inhibit TGF-beta 1 signaling; however, ectopic expression of ZEB1 reactivated TGF-beta 1 signaling by binding to Smad7 and recruiting the Smad3/p300 histone acetyltransferase complex to the promoter after TGF-beta 1 stimulation in ATLL. Conversely, because ZEB1 mRNA was detected in the late stages of T-cell development, we used CTLL2 cells with ZEB1 expression, a murine peripheral T-cell lymphoma, and found that a complex of Smad3, Smad7 and ZEB1 was bound to the SRE of the p21(CDKN1A) promoter after the induction of Smad7 by TGF-beta 1 treatment. Because the duration of TGF-beta 1-induced transcriptional activation of PAI-1 and p21 was shortened in shZEB1-expressing CTLL2 cells, ZEB1 may have a role in enhancing TGF-beta 1 signaling by binding not only to Smad3 but also to Smad7 in the nucleus. Altogether, these results suggest that both ZEB1 downregulation and Smad7 overexpression contribute to resistance to TGF-beta 1-mediated growth suppression in ATLL. Oncogene ( 2010) 29, 4157-4169; doi: 10.1038/onc.2010.172; published online 31 May 2010