Abstract
Metastatic cancer remains a clinical challenge; however, patients diagnosed prior to metastatic dissemination have a good prognosis. The transcription factor, TWIST1 has been implicated in enhancing the migration and invasion steps within the metastatic cascade, but the range of TWIST1-regulated targets is poorly described. In this study, we performed expression profiling to identify the TWIST1-regulated transcriptome of melanoma cells. Gene ontology pathway analysis revealed that TWIST1 and epithelial to mesenchymal transition (EMT) were inversely correlated with levels of cell adhesion molecule 1 (CADM1). Chromatin immunoprecipitation (ChIP) studies and promoter assays demonstrated that TWIST1 physically interacts with the CADM1 promoter, suggesting TWIST1 directly represses CADM1 levels. Increased expression of CADM1 resulted in significant inhibition of motility and invasiveness of melanoma cells. In addition, elevated CADM1 elicited caspase-independent cell death in non-adherent conditions. Expression array analysis suggests that CADM1 directed non-adherent cell death is associated with loss of mitochondrial membrane potential and subsequent failure of oxidative phosphorylation pathways. Importantly, tissue microarray analysis and clinical data from TCGA indicate that CADM1 expression is inversely associated with melanoma progression and positively correlated with better overall survival in patients. Together, these data suggest that CADM1 exerts tumor suppressive functions in melanoma by reducing invasive potential and may be considered a biomarker for favorable prognosis.
Highlights
Patients presenting with early stage cancers who undergo surgical intervention have a favorable overall survival
Genes from the epithelial to mesenchymal transition (EMT) hallmark pathway with an absolute Pearson correlation value of >0.9 were listed with the associated rvalue and heatmap representation of expression (Fig. 1d). These results suggest that TWIST1 regulates EMT pathway-related genes in melanoma
We focused on oxidative phosphorylation since it has been linked to adhesion-related effects on cell survival in breast cancer[39] and cell adhesion molecule 1 (CADM1) plays a role in mitochondrial biology in human lung papillary adenocarcinoma[40]
Summary
Patients presenting with early stage cancers who undergo surgical intervention have a favorable overall survival. By contrast the prognosis for patients with metastatic disease is poor. Metastatic progression is a complex process that includes the ability to migrate and invade through the in situ organ, intravasate into vasculature, resist anoikis to survive in the bloodstream, and extravasate for colonization of a distant organ[1]. Associated with the initial migration and invasion, tumor cells need to alter a gene expression program, collectively. TWIST1 contributes to an EMT-like phenotype switch in melanoma that enhances migratory and invasive function[5,6]. Our group has previously demonstrated that TWIST1 plays a role in the ability of melanoma cells to invade through the dermal layer in part by up-regulating the matrix metalloprotease, MMP-17.
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