GREB1 isoform 4 is specifically transcribed by MITF and required for melanoma proliferation

Oncogene. 2023 Oct;42(42):3142-3156. doi: 10.1038/s41388-023-02803-6. Epub 2023 Sep 1.


Growth regulation by estrogen in breast cancer 1 (GREB1) is involved in hormone-dependent and -independent tumor development (e.g., hepatoblastoma). In this study, we found that a GREB1 splicing variant, isoform 4 (Is4), which encodes C-terminal half of full-length GREB1, is specifically expressed via microphthalmia-associated transcription factor (MITF) in melanocytic melanoma, and that two MITF-binding E-box CANNTG motifs at the 5'-upstream region of GREB1 exon 19 are necessary for GREB1 Is4 transcription. MITF and GREB1 Is4 were strongly co-expressed in approximately 20% of the melanoma specimens evaluated (17/89 cases) and their expression was associated with tumor thickness. GREB1 Is4 silencing reduced melanoma cell proliferation in association with altered expression of cell proliferation-related genes in vitro. In addition, GREB1 Is4 targeting by antisense oligonucleotide (ASO) decreased melanoma xenograft tumor formation and GREB1 Is4 expression in a BRAFV600E; PTENflox melanoma mouse model promoted melanoma formation, demonstrating the crucial role of GREB1 Is4 for melanoma proliferation in vivo. GREB1 Is4 bound to CAD, the rate-limiting enzyme of pyrimidine metabolism, and metabolic flux analysis revealed that GREBI Is4 is necessary for pyrimidine synthesis. These results suggest that MITF-dependent GREB1 Is4 expression leads to melanoma proliferation and GREB1 Is4 represents a new molecular target in melanoma.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Melanoma* / genetics
  • Melanoma* / metabolism
  • Mice
  • Microphthalmia-Associated Transcription Factor* / genetics
  • Microphthalmia-Associated Transcription Factor* / metabolism
  • Neoplasm Proteins / genetics
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Pyrimidines


  • Microphthalmia-Associated Transcription Factor
  • Protein Isoforms
  • Pyrimidines
  • MITF protein, human
  • GREB1 protein, human
  • Neoplasm Proteins