Malignant melanoma is one of the most aggressive types of human cancers. Its ability to metastasize in combination with resistance to conventional anticancer chemotherapy makes melanoma extremely difficult to cure. As a consequence, the median survival of patients with metastatic melanoma is merely 8.5 months. Melanoma cell invasion, a prerequisite for metastases, often includes loss of a cell-cell adhesion molecule E-cadherin (CDH1). In epithelial cells, loss of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), a process by which static epithelial cells acquire a mesenchymal-like phenotype, including migratory capability. In carcinomas, EMT promotes invasive phenotypes which are essential for metastatic dissemination. In search for transcription factors regulating the EMT-like transition in melanoma cells, we evaluated several bona fide regulators of carcinoma EMT. One of them, FOXQ1, a member of FOX family of transcription factors, is overexpressed at advanced stages in multiple human carcinomas. FOXQ1 promotes EMT through upregulation of EMT transcription factors (EMT-TF) ZEB2 and TWIST1, ultimately resulting in repression of CDH1. Unexpectedly, we found that FOXQ1 expression is strongly inhibited in metastatic melanoma cells compared to normal human melanocytes (NHM). Accordingly, TCGA data analysis revealed that FOXQ1 levels are significantly lower in metastatic melanoma specimens compared to primary melanomas. Moreover, TCGA-based analysis and published studies identified that levels of several other EMT-TFs that are higher in metastatic vs primary carcinomas are instead lower in metastatic vs primary melanomas.. We found that restoration of FOXQ1 levels suppresses malignant phenotypes in all tested melanoma cells independent of their status of microphthalmia-associated transcription factor (MITF), a transcription factor essential for the development of the melanocyte lineage. Moreover, FOXQ1 inhibits multiple transformed phenotypes via MITF-dependent and -independent pathways. Therefore, we will identify mechanisms of FOXQ1 tumor suppressor activities in human melanoma cells and determine the role of Foxq1 deficiency in promotion of melanomagenesis in a mouse model of melanoma. In addition to the mechanistic analysis of a novel tumor suppressor in melanoma cells, our studies will shed light on an intriguing mechanism of how a transcriptional regulator can act as a tumor suppressor or as an oncogene at the same stage of tumor progression depending on the tissue origin of cancer.
Metastatic melanoma is one of the most aggressive types of human cancers. Its ability to metastasize in combination with resistance to conventional anticancer chemotherapy makes melanoma extremely difficult to cure. As a consequence, the median survival of patients with metastatic melanoma is merely 8.5 months. Melanoma possesses one of the highest metastatic potentials among human cancers. Acquisition of invasive phenotypes is a prerequisite for melanoma metastases. Elucidation of the molecular mechanisms underlying melanoma invasion will greatly enhance the design of novel agents for melanoma therapeutic intervention. We have recently identified that transcription factor FOXQ1 suppresses melanoma cell invasion and tumorigenicity. Our proposal is aimed at the identification of the mechanism of FOXQ1 melanoma suppressor activity in human melanoma cells and in a mouse model of melanoma.
| Bagati, Archis; Bianchi-Smiraglia, Anna; Moparthy, Sudha et al. (2017) Melanoma Suppressor Functions of the Carcinoma Oncogene FOXQ1. Cell Rep 20:2820-2832 |
