Malignant phenotypes in metastatic melanoma are governed by SR-BI and its association with glycosylation and STAT5 activation

Katharina Kinslechner, David Schörghofer, Birgit Schütz, Maria Vallianou, Bettina Wingelhofer, Wolfgang Mikulits, Clemens Röhrl, Markus Hengstschläger, Richard Moriggl, Herbert Stangl, Mario Mikula

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Metastatic melanoma is hallmarked by elevated glycolytic flux and alterations in cholesterol homeostasis. The contribution of cholesterol transporting receptors for the maintenance of a migratory and invasive phenotype is not well defined. Here, the scavenger receptor class B type I (SCARB1/SR-BI), a high-density lipoprotein (HDL) receptor, was identified as an estimator of melanoma progression in patients. We further aimed to identify the SR-BI-controlled gene expression signature and its related cellular phenotypes. On the basis of whole transcriptome analysis, it was found that SR-BI knockdown, but not functional inhibition of its cholesterol-transporting capacity, perturbed the metastasis-associated epithelial-tomesenchymal transition (EMT) phenotype. Furthermore, SR-BI knockdown was accompanied by decreased migration and invasion of melanoma cells and reduced xenograft tumor growth. STAT5 is an important mediator of the EMT process and loss of SR-BI resulted in decreased glycosylation, reduced DNA binding, and target gene expression of STAT5. When human metastatic melanoma clinical specimens were analyzed for the abundance of SR-BI and STAT5 protein, a positive correlation was found. Finally, a novel SR-BI-regulated gene profile was determined, which discriminates metastatic from nonmetastatic melanoma specimens indicating that SR-BI drives gene expression contributing to growth at metastatic sites. Overall, these results demonstrate that SR-BI is a highly expressed receptor in human metastatic melanoma and is crucial for the maintenance of the metastatic phenotype. Implications: High SR-BI expression in melanoma is linked with increased cellular glycosylation and hence is essential for a metastasis-specific expression signature.

Original languageEnglish
Pages (from-to)135-146
Number of pages12
JournalMolecular Cancer Research
Volume16
Issue number1
DOIs
Publication statusPublished - Jan 2018
Externally publishedYes

Keywords

  • Animals
  • Cell Line, Tumor
  • Cell Movement/physiology
  • Female
  • Glycosylation
  • Heterografts
  • Humans
  • Melanoma/genetics
  • Mice
  • Mice, SCID
  • Phenotype
  • RNA, Messenger/genetics
  • Receptors, LDL/biosynthesis
  • STAT5 Transcription Factor/metabolism
  • Scavenger Receptors, Class B/biosynthesis
  • Transfection

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