Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma

Abstract

High malignancy and early metastasis are hallmarks of melanoma. Here, we report that the transcription factor Snail1 inhibits expression of the tumor suppressor CYLD in melanoma. As a direct consequence of CYLD repression, the protooncogene BCL-3 translocates into the nucleus and activates Cyclin D1 and N-cadherin promoters, resulting in proliferation and invasion of melanoma cells. Rescue of CYLD expression in melanoma cells reduced proliferation and invasion in vitro and tumor growth and metastasis in vivo. Analysis of a tissue microarray with primary melanomas from patients revealed an inverse correlation of Snail1 induction and loss of CYLD expression. Importantly, tumor thickness and progression-free and overall survival inversely correlated with CYLD expression. Our data suggest that Snail1-mediated suppression of CYLD plays a key role in melanoma malignancy.

NF-κB-induced KIAA1199 promotes survival through EGFR signalling

“…As we demonstrated here that BCL-3-deficient CaSki cells have decreased expression of fibronectin and because mesenchymal markers are not properly expressed on KIAA1199 deficiency in cervical cancer cells, our data defined BCL-3 as an oncogenic protein that promotes EMT, at least by controlling KIAA1199 expression. As BCL-3 also directly drives N-cadherin expression in melanoma-derived cells56 and because KIAA1199-depleted CaSki cells had decreased N-cadherin expression despite intact BCL-3 protein levels, we conclude that BCL-3 controls the expression of mesenchymal markers through multiple mechanisms in transformed cells. Given the capacity of HPV16 E6/E7 proteins to trigger EMT through decreased E-cadherin expression in immortalized keratinocytes5758, our data also suggest that KIAA1199, whose expression is correlated with HPV status, links E6 expression to EMT.…”

microRNA-340 as a modulator of RAS–RAF–MAPK signaling in melanoma

“…As a first step to better understand the involvement of miR-340 in melanoma pathogenesis, we evaluated the expression of miR-340 in a panel of melanoma cells, depicted in Figure 1. The panel of cell lines comprises NHEMs and melanoma cell lines representing early stage radial growth phase (WM35, BRAF V600E mutation) and vertical growth phase (WM115, BRAF V600E mutation) as well as metastatic melanoma cell lines with mutations in NRAS Q61R (SK-MEL-2) and BRAF V600E (SK-MEL-28, Mel 928, Mel Ju, 451 Lu) or wild type for NRAS and BRAF (Hs294T) [12, 33–39]. Contrary to our expectations, miR-340 was significantly elevated in all of the melanoma cell lines, compared to NHEMs.…”

Hypoxia suppresses cylindromatosis (CYLD) expression to promote inflammation in glioblastoma: possible link to acquired resistance to anti-VEGF therapy

“…As of today, little is still known about transcriptional regulation of CYLD. However, CYLD mRNA transcription is directly inhibited by Snail [28] and the Notch target Hes1 [29], both of which are up-regulated and activated under hypoxic conditions [34, 35]. Another finding worth noting is that hypoxia stimulates human papilloma virus-encoded E6 protein to promote ubiquitination and proteasomal degradation of CYLD in human papilloma virus-positive squamous cell carcinoma cell lines [36].…”

“…CYLD regulates diverse biological processes including cell proliferation, survival, and migration; immune responses; osteoclastogenesis; and spermatogenesis [26]. With regard to malignancies, reduced expression and mutation of CYLD, with tumor-promoting effects, were reported for several cancers including melanoma, T-cell leukemia, hepatocellular carcinoma, and breast cancer [28-31]. CYLD expression was recently shown to be reduced in gliomas, with an inverse correlation with tumor grade and prognosis [32].…”