A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity

Abstract

Loss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K–AKT–GSK3β axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent β-catenin transcriptional modulation in vitro, cooperates with NRASQ61K to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-β–catenin axis is mediated by a feedback loop in which β-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of β-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis.

Knockdown of Sall4 inhibits intrahepatic cholangiocarcinoma cell migration and invasion in ICC-9810 cells

“…We also found that knockdown of Sall4 directly increased Bmi-1 expression by activating the promoter activity of Bmi-1 in ICC cells, indicating that Bmi-1 was a direct Sall4 target gene in several types of cancers. In addition, Bmi-1 can decrease GSK3β, the component of Axin/GSK3β/APC complex, to prevent the degradation of β-catenin, leading to activation of Wnt/β-catenin signaling in breast cancer 23,24. Interestingly, β-catenin is inactivated as a substrate of AKT 24.…”

Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma

“…The long latency in these models (>10 months) indicates that additional genomic alterations are required for tumor progression. Loss-of-function mutations in phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), or cyclin-dependent kinase inhibitor 2A (INK4A) and transformation related protein 53 (TRP53), events that are frequently observed in human melanoma (16), have been shown to increase the penetrance and reduce the latency of these BRAF V600E -and/or NRAS Q61K -driven mouse melanoma lesions (13,14,(17)(18)(19)(20). Importantly, since these melanoma lesions develop in the absence of UV exposure, the background mutation frequency is likely to be dramatically reduced.…”

Direct interaction between miR-203 and ZEB2 suppresses epithelial–mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance

“…miR-203 has been previously implicated in the pathogenesis of many tumor types including colorectal cancer [1], gastric cancer [2], breast cancer [3], melanoma [4], and liver cancer [5]. In lung cancer, miR-203 functions as a tumor suppressor which represses cell proliferation and metastasis [6] by targeting Bmi1 and PKCα [7,8].…”