The effect of CTBP dehydrogenase inhibitors MTOB and 4-Cl-HIPP in J774.1 cells

C-terminal binding proteins (CTBPs) are conserved transcriptional repressors involved in cancer and inflammation. Uniquely amongst transcriptional coregulators, CTBPs possess a functional dehydrogenase domain. Since multiple malignancies display elevated CTBP levels, CTBP inhibitors targeting this dehydrogenase domain have been developed. While the importance of CTBPs dehydrogenase function for transcriptional regulation remains unclear, multiple studies have relied CTBP inhibitors such as MTOB and 4-Cl-HIPP. In vitro studies have confirmed binding of these compounds to CTBP’s active site, however evidence for specificity is currently lacking. To address this, we treated wildtype or Ctbp1, 2 double knockout J774.1 cells with MTOB or 4-Cl-HIPP and performed RNAseq. We observed that both inhibitors elicit distinct transcriptional changes indicating non-overlapping modes of action. Moreover, the majority of changes induced by either inhibitor are observed in knockout cells indicative of off-target effects. We hypothesize that those CTBP dehydrogenase inhibitors might lack specificity to CTBPs.