The Hedgehog/GLI signaling pathway activates transcription of Slug (Snail2) in melanoma cells

Abstract

In melanoma and other cancers, invasion, epithelialto-mesenchymal transition, metastasis and cancer stem cell maintenance are regulated by transcription factors including the Snail family. Slug (Snail2) protein generally supports migration and apoptosis resistance. However, its role in melanoma is not completely understood. The present study investigated the transcriptional regulation of the SLUG gene in melanoma. It demonstrated that SLUG is under the control of the Hedgehog/GLI signaling pathway and is activated predominantly by the transcription factor GLI2. The SLUG gene promoter contains a high number of GLI-binding sites. Slug expression is activated by GLI factors in reporter assays and inhibited by GANT61 (GLI inhibitor) and cyclopamine (SMO inhibitor). SLUG mRNA levels are lowered by GANT61 as assessed by reverse transcription-quantitative PCR. Chromatin immunoprecipitation revealed abundant binding of factors GLI1-3 in the four subregions of the proximal SLUG promoter. Notably, melanoma-associated transcription factor (MITF) is an imperfect activator of the SLUG promoter in reporter assays, and downregulation of MITF had no effect on endogenous Slug protein levels. Immunohistochemical analysis confirmed the above findings and showed MITF-negative regions in metastatic melanoma that were positive for GLI2 and Slug. Taken together, the results demonstrated a previously unrecognized transcriptional activation mechanism of the SLUG gene, which may represent its main regulation of expression in melanoma cells.

The anti-tumor activity of tangeretin in esophageal squamous cell carcinoma by inhibiting GLI2-mediated transcription of GPNMB

“…identified as target genes of GLI2 TF [39,40]. Our data also uncovered the repression of Tan in the expression of Slug, Snail, VEGF, and Cyclin D1 in ESCC cells (S2 Fig) , suggesting that Tan may downregulate their expression via GLI2 and thus influences ESCC metastasis.…”

“…More intriguingly, our study defines the causal association between the reduction of GPNMB and the anti-migration and anti-invasion functions of Tan in TE-1 and KYSE150 ESCC cells. Some important metastasis-related markers, such as EMT specific molecule Snail, angiogenesis-related molecule VEGF, and cell cycle regulator Cyclin D1, have been identified as target genes of GLI2 TF [ 39 , 40 ]. Our data also uncovered the repression of Tan in the expression of Slug, Snail, VEGF, and Cyclin D1 in ESCC cells ( S2 Fig ), suggesting that Tan may downregulate their expression via GLI2 and thus influences ESCC metastasis.…”

SNAI2 enhances HPV‑negative cervical cancer cell dormancy by modulating u‑PAR expression and the activity of the ERK/p38 signaling pathway in vitro

“…Notably, the ERK MAPK /p38 SAPK activity ratio predicts whether cells proliferate or enter a state of dormancy ( 20 ); a high ratio favors tumor growth, whereas a low ratio promotes tumor growth arrest (dormancy). ERK is negatively regulated by p38MAPK in breast cancer, prostate cancer, melanoma and fibrosarcoma cell lines ( 31 ), with u-PAR being a crucial modulator of this process ( 21 ). However, whether the ERK and p38 pathway participates in regulating SNAI2-mediated dormancy in HPV-negative cervical cancer cells remains to be determined.…”