Malignant Phenotypes in Metastatic Melanoma are Governed by SR-BI and its Association with Glycosylation and STAT5 Activation

Mol Cancer Res. 2018 Jan;16(1):135-146. doi: 10.1158/1541-7786.MCR-17-0292. Epub 2017 Oct 3.


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-to-mesenchymal 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. Mol Cancer Res; 16(1); 135-46. ©2017 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • LDLR protein, human
  • RNA, Messenger
  • Receptors, LDL
  • SCARB1 protein, human
  • STAT5 Transcription Factor
  • Scavenger Receptors, Class B