CADM1 is a TWIST1-regulated suppressor of invasion and survival

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.

MicroRNA‑214 promotes the EMT process in melanoma by downregulating CADM1 expression

“…For instance, overexpression of cadM1 inhibits cell-cycle progression and invasion of hepatocellular carcinoma (11). Moreover, the present results indicated that cadM1 acted as a tumor suppressor in melanoma, which was similar to the results of a previous study (9). Furthermore, overexpression of cadM1 significantly inhibited the eMT process of melanoma.…”

“…Cell adhesion molecule 1 (CADM1), which is regarded as a suppressor gene in the tumorigenesis of non-small cell lung cancer, has been identified as a diagnostic marker for adult T-cell leukemia and lymphoma ( 8 ). In addition, it has been previously reported that CADM1 plays an inhibitory role in the progression, migration and invasion of cancer, such as cervical cancer and liver cancer ( 9 – 11 ), indicating that CADM1 is an inhibitor of tumor cell malignant features. You et al ( 12 ) showed that CADM1 was differentially expressed in melanoma, but its function in melanoma remains unknown.…”

Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy

“…Moreover, RUXF and PGES2 are known to be involved in chemo-resistance in ovarian and colorectal cancer, respectively (18,19). On the other hand, CADM1 is shown to be a good prognostic marker in other cancers (20,21). Four proteins (i.e., TMED2, AGR2, JTB, and CADM1) among the over-expressed proteins in poor-responders ( Table 3) were predicted to be secreted extracellularly.…”

Impact of Sustained Transforming Growth Factor-β Receptor Inhibition on Chromatin Accessibility and Gene Expression in Cultured Human Endometrial MSC

“…Another potential mechanism that promotes survival of A83-01-treated eMSC involves closure of the proximal promoter of CADM1 , which encodes a potent inhibitor of cell proliferation and migration ( Murakami, 2005 ). CADM1 repression is mediated by TWIST1 ( Hartsough et al, 2019 ), a TF upregulated in eMSC in response to A83-01 treatment ( Gurung et al, 2018b ). The altered cis-regulatory chromatin landscape in response to A83-01-induced TGFβ-R blockade also suggested that silencing of specific TFs may be essential to maintain cultured eMSC in an undifferentiated state.…”