Circ-GLI1 promotes metastasis in melanoma through interacting with p70S6K2 to activate Hedgehog/GLI1 and Wnt/β-catenin pathways and upregulate Cyr61

Cell Death Dis. 2020 Jul 30;11(7):596. doi: 10.1038/s41419-020-02799-x.

Abstract

Circular RNAs (circRNAs) are emerging regulators in the development of human cancers. However, the role of circRNAs in melanoma is poorly understood. Microarray analysis and qRT-PCR was applied to screen out circRNAs that were differentially expressed in melanoma cells compared to normal cells. Currently, we first proved that inhibition of CYR61, an angiogenesis factor with controversial functions in melanoma, restrained cell migration, invasion and angiogenesis in melanoma. Thereafter, a novel circRNA hsa_circ_0027247 derived from GLI1 (circ-GLI1) was identified to positively modulate CYR61 expression in melanoma cell lines. Besides, silencing circ-GLI1 hindered melanoma cell metastasis as well. Interestingly, we unveiled that circ-GLI1 enhanced CYR61 transcription by an indirect manner. Meanwhile, circ-GLI1 activated Hedgehog/GLI1 and Wnt/β-catenin pathways by affecting the degradation of GLI1 and β-catenin. Moreover, we found that circ-GLI1 interacted with p70S6K2 to induce GSK3β phosphorylation at Ser9, and therefore blocked the binding of GSK3β with GLI1 and β-catenin so as to elevate their protein expression. Of note, CYR61 was transcriptionally activated by MYC, a well-recognized downstream target of both GLI1 and β-catenin. In conclusion, circ-GLI1 exacerbates the metastasis and angiogenesis of melanoma by upregulating Cyr61 via p70S6K2-dependent activation of Hedgehog/GLI1 and Wnt/β-catenin pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cysteine-Rich Protein 61 / genetics*
  • Cysteine-Rich Protein 61 / metabolism
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Glycogen Synthase Kinase 3 beta / metabolism
  • HEK293 Cells
  • Hedgehog Proteins / metabolism*
  • Humans
  • Male
  • Melanoma / genetics*
  • Melanoma / pathology
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / genetics
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Circular / genetics
  • RNA, Circular / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Up-Regulation / genetics*
  • Wnt Signaling Pathway*
  • Zinc Finger Protein GLI1 / metabolism*

Substances

  • CCN1 protein, human
  • Cysteine-Rich Protein 61
  • Hedgehog Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Circular
  • Zinc Finger Protein GLI1
  • Glycogen Synthase Kinase 3 beta
  • Ribosomal Protein S6 Kinases, 70-kDa