TI - Discussion . AB - CtBP1 is a known co-repressor involved in gene regulation with several other transcription factors . Recently , we described the loss of CtBP1 expression in melanoma [4] . In this study , we aimed to evaluate the importance of this loss and subsequent changes to regulated genes in more detail . Interestingly , Western blot and RT-PCR studies revealed the existence of a CtBP1 splice variant (CtBP1splice) in melanoma cells . This variant lacks exon 4 ( in frame ) leading to a CtBP1 variant missing aa 114-182 , and does not bind TCF4 or Snail suggesting that CtBP1 co-repressor activity may not be fulfilled by this variant . However , expression of the variant seems to be important in tumors as CtBP1splice was also detected in breast , colon and hepatocellular carcinoma cells which lack full length CtBP1 expression ( data not shown ) . Several other splice forms of CtBP1 have been previously detailed [14] , however the splice variant we describe is novel . The lack of the PAK PHOSphorylation site could lead to changes in the control of nuclear-to-cytosolic translocation and co-repressor function [15] . In addition , NAD binding to CtBP1 and CtBP1 dimerization may be affected . As NAD(H) -dependent dimerization is required for transcriptional repression , repressor functions could also be influenced . Additionally , changes in the two protein binding sites could impact the binding of transcription factors to CtBP1splice [16,17] . CtBP1splice expression after reduction of full length CtBP1 could be important in tumor cells due to general functions recently been described for CtBP as CtBP1 was shown to be involved in Golgi morphogenesis by association to centrosomes [18] and in vesicular trafficking . Interestingly , some publications also hint at a role for CtBP as a tumor promoter [1] . Jin et al .describe upregulation of MDR1 by CtBP1 leading to drug resistance [19] . This effect could not be shown to be modulated by histone modification which led the authors to suggest regulation via CtBP1 by an unknown mechanism . In addition , CtBP1 was shown to activate expression of Wnt genes in a TCF-independent manner [20] . It can only be speculated that these tumor promoting effects can be achieved by CtBP1splice . Further studies are necessary to understand the function and role of CtBP1splice in carcinogenesis . CtBP1 has been speculated to be involved in normal cell growth control . It was shown previously that the binding of CtBP to adenoviral E1A correlates with inhibition of E1A and H-ras cotransformation , tumorigenesis and metastasis [21] . Furthermore , a repressor function of CtBP on E2F-medited transcription via RB was detected [22] . In our study , proliferation was unchanged after reexpression of CtBP1 whereas migration and invasion assays pointed to a role of CtBP1 in cell migration as reexpression of CtBP1 induced a reduction of the migratory potential . This finding was further supported by detailed analysis of CtBP1 -regulated genes . By comparison of genes carrying a LEF/TCF site with cDNA array data ( GDS1989 ) [11] on melanoma fourteen genes showing a correlation with melanoma development and progression were determined . Regulation of these genes by CtBP1 was confirmed performing quantitative RT-PCR . Interestingly , expression of most CtBP1 -regulated genes discussed here is associated with the invasive state recently described by Hoek and co-workers [12] . This supports the finding that loss of CtBP1 enhances the migratory behavior of cells . Only two of the CtBP1 -regulated genes were previously described as playing a role in melanoma . ENPP2 (Autotaxin) was originally isolated from melanoma cells and shown to augment the invasive potential of melanoma cells by inducing uPA expression [23,24] . Versican was also previously described to be expressed in melanoma and to be an inducer of metastasis [25] . The remaining genes have not previously been described to play a role in melanoma , however , deregulation and implication in other kinds of cancer has been noted . ATP1B1 , an Na2K-ATPase , was found to be involved in progression and metastasis of prostate cancer [26] . Collagen type I alpha2 and FUS were found to be deregulated in gastric cancer and speculated to play a role in invasion and metastasis [27] . Changes in Claudin 11 were shown during progression of epithelial tumors leading to acquisition of migratory potential [28] . Upregulation of ENC1 , an actin-binding protein , contributes to colorectal carcinogenesis [29] . Regulation of ENC1 gene expression by LEF/TCF was already shown . FAT , a cadherin-family molecule and FCSN1 , a protein involved in the assembly of actin filament bundles , were described to play a role in general cell migratory processes [30,31] . Enhanced FSCN1 expression was associated with increased invasiveness in urinary cancer . TMED4 was significantly induced in invasive adenocarcinoma [32] . In summary , the data available on the functional role of CtBP1 -regulated genes hint to an implication in migratory and invasive processes . It therefore appears that loss of the CtBP1 co-repressor function may be a critical event in the pathogenesis of melanoma . In future , it would be highly interesting to extend the analysis and perform in vivo analysis to look at effects of full length CtBP1 upon tumor growth in a nude mouse model .