Abstract 4089: CADM1 is a TWIST1 regulated suppressor of melanoma invasion

Abstract

Abstract Melanoma is the deadliest form of skin cancer; however, with early detection prior to metastatic dissemination, patients generally have a good prognosis. Recently, our lab has implicated the transcription factor TWIST1 in the progression of melanoma towards metastasis. In melanoma cells, we found that RAS-RAF-MEK-ERK (ERK1/2 pathway) signaling increases TWIST1 expression, which promotes invasive properties in the dermal microenvironment at least in part by enhancing levels of the matrix metalloproteinase, MMP1. Other TWIST1 regulated targets are poorly described. In this study, we compared expression profiling data from cells expressing shRNA against TWIST1 or cells overexpressing TWIST1 in order to determine TWIST1 regulated genes. KEGG and GO analysis revealed that TWIST1 is responsible for regulating a number of genes involved in cellular adhesion. We found that TWIST1 levels inversely correlate with levels of cell adhesion molecule 1 (CADM1) (NECL-2, IGSF4, TSLC1, SynCAM). Chromatin immunoprecipitation (ChIP) studies and promoter assays demonstrate that TWIST1 physically interacts with CADM1 promoter and this is associated with reduced CADM1 levels. Additionally, CADM1 expression is inversely associated ERK1/2 signaling and TWIST1 expression. Modulation of cellular CADM1 levels does not seem to affect proliferations rates however, overexpression of CADM1 augments cell-cell interaction, and cell aggregation. Furthermore, exogenous CADM1 inhibited serum directed migration and invasion through matrigel coated boyden chambers, while knockdown of CADM1 was associated with an enhancement in the migratory and invasion properties. Taken together, these data provide evidence that CADM1 is negatively regulated by TWIST1, and may act as a suppressor of melanoma invasion. Citation Format: Edward J. Hartsough, Michele B. Weiss, Curtis H. Kugel, Sheera R. Rosenbaum, Andrew E. Aplin. CADM1 is a TWIST1 regulated suppressor of melanoma invasion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4089. doi:10.1158/1538-7445.AM2015-4089