CtBP1 interacts with Ikaros and modulates pituitary tumor cell survival and response to hypoxia

Abstract

C-terminal binding protein (CtBP) is a transcriptional corepressor that plays an important role in mammalian development and tumorigenesis. We demonstrate that CtBP is expressed in adenohypophyseal cells and is expressed at high levels in human corticotroph, somatotroph, and lactotroph pituitary adenomas. CtBP interacts with Ikaros isoforms in GH4 and AtT20 pituitary tumor cells. Ikaros and CtBP1 expression is coordinately induced by hypoxia, and this response is abrogated by CtBP1 deficiency. Forced reduction of CtBP1 leads to reduced cell growth, up-regulation of Sprouty 2, and down-regulation of ectonucleotide pyrophosphatase phosphodiesterase 2 (Enpp2). Consistent with diminished Enpp2 activity, CtBP1-deficient pituitary cells are more susceptible to hypoxia-induced apoptosis, which is rescued by Enpp2-derived lysophosphatidic acid treatment. These results identify putative oncogenic properties of CtBP1 and provide new insights into the overlapping functions of two members of the chromatin remodeling network in the response to hypoxic pituitary tumor cell drive.