A Trichostatin A (TSA)/Spl-mediated mechanism for the regulation of SALL2 tumor suppressor in Jurkat T cells

Abstract

SALL2 is a transcription factor involved in development and disease. Deregulation of SALL2 has been associated with cancer, suggesting that it plays a role in the disease. However, how SALL2 is regulated and why is de-regulated in cancer remain poorly understood. We previously showed that the p53 tumor suppressor represses SALL2 under acute genotoxic stress. Here, we investigated the effect of Histone Deacetylase Inhibitor (HDACi) Trichostatin A (TSA), and involvement of Spl on expression and function of SALL2 in Jurkat T cells. We show that SALL2 mRNA and protein levels were enhanced under TSA treatment. Both, TSA and ectopic expression of Spl transactivated the SALL2 P2 promoter. This transactivation effect was blocked by the Spl-binding inhibitor mithramycin A. Spl bound in vitro and in vivo to the proximal region of the P2 promoter. TSA induced Spl binding to the P2 promoter, which correlated with dynamic changes on H4 acetylation and concomitant recruitment of p300 or HDAC1 in a mutually exclusive manner. Our results suggest that TSA-induced Spl-Lys703 acetylation contributes to the transcriptional activation of the P2 promoter. Finally, using a CRISPR/Cas9 SALL2-KO Jurkat-T cell model and gain of function experiments, we demonstrated that SALL2 upregulation is required for TSA-mediated cell death. Thus, our study identified Spl as a novel transcriptional regulator of SALL2, and proposes a novel epigenetic mechanism for SALL2 regulation in Jurkat-T cells. Altogether, our data support SALL2 function as a tumor suppressor, and SALL2 involvement in cell death response to HDACi.