Abstract 273: Transcriptional regulation of L1CAM in endometrial cancer

Abstract

Abstract The L1 cell adhesion molecule (L1CAM, CD171) was initially described as a cell surface protein in the developing nervous system involved in neural outgrowth and axon guidance. During the last years it became evident that high expression levels of L1CAM are observed in many human carcinomas and are linked to tumor progression. L1CAM expression in tumors can augment cell motility and invasive potential and lead to constitutive NFκB activation. We showed before that in endometrial cancer (EC) the expression of L1CAM was correlated with poor prognosis. ECs can be subdivided in two types; a less aggressive type I and a highly aggressive type II. We showed that L1CAM expression was absent in type I ECs, whereas all cases of type II tumors (n=272) were L1CAM positive. We also provided evidence that in L1CAM-negative EC cell lines L1CAM expression can be upregulated by TGF-b1 treatment involving the transcription factor SLUG. In the present study, we have investigated additional mechanisms that can affect L1CAM expression. These mechanisms involve the modification of histone proteins and their packaging to the DNA as well as the direct modification of the DNA by DNA-methyltransferases (DNMTs). We show that the treatment of EC cell lines with Histon-deacetylase-Inhibitors (HDACIs) and/or DNMT inhibitors lead to increased L1CAM expression at the mRNA and protein level. Furthermore, we observed that the methylation pattern of the L1CAM-promoter differed between L1CAM positive and negative cell lines. The RE-1 silencing transcription factor (REST) complex seems to be responsible for the silencing of the L1CAM expression in non-neuronal tissues. The REST complex is associated with chromatin-remodeling complexes, the recruitment of HDACs as well as DNMTs and thereby leads to the silencing of the respective promoter element. We observed that the knockdown of REST in L1CAM negative EC cell lines leads to a dramatic increase in L1CAM expression. Likewise the overexpression of REST in L1CAM positive EC cell lines diminished L1CAM expression. We conclude that the loss or reduced expression of REST in concert with epigenetic elements could represent an additional and novel mechanism to cause aberrant L1CAM expression in ECs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 273. doi:1538-7445.AM2012-273