Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-beta1-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-beta1 (TGF-beta1) 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-beta1. A protein complex of Smad7 and histone deacetylase constantly bound to the promoter region of TGF-beta1 responsive genes with the Smad-responsive element (SRE) to inhibit TGF-beta1 signaling; however, ectopic expression of ZEB1 reactivated TGF-beta1 signaling by binding to Smad7 and recruiting the Smad3/p300 histone acetyltransferase complex to the promoter after TGF-beta1 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-beta1 treatment. Because the duration of TGF-beta1-induced transcriptional activation of PAI-1 and p21 was shortened in shZEB1-expressing CTLL2 cells, ZEB1 may have a role in enhancing TGF-beta1 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-beta1-mediated growth suppression in ATLL.