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Updated: Jul 27, 2025
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation
Yonghwan Shin1, Sungmin Kim1, Gangning Liang1
1University of Southern California.
Background:
Melanoma is the most aggressive form of skin cancer arising from pigment-producing melanocytes and is often associated with dysregulation of epigenetic factors targeting histones. VprBP, also known as DCAF1, is a recently identified kinase and plays an important role in downregulating the transcription of tumor suppressor genes as well as increasing the risk for colon and prostate cancers. However, it remains unknown whether VprBP is also involved in triggering the pathogenesis of other types of cancer.
Results:
We demonstrate that VprBP is highly expressed and phosphorylates threonine 120 (T120) on histone H2A to drive transcriptional inactivation of growth regulatory genes in melanoma cells. As is the case for its epigenetic function in colon and prostate cancers, VprBP acts to induce gene silencing program dependently of H2AT120 phosphorylation (H2AT120p). The significance of VprBP-mediated H2AT120p is further underscored by the fact that VprBP knockdown- or VprBP inhibitor-induced lockage of H2AT120p mitigates melanoma tumor growth in xenograft models. Moreover, artificial tethering of VprBP wild type, but not VprBP kinase-dead mutant, to its responsive genes is sufficient for achieving an inactive transcriptional state in VprBP-depleted cells, indicating that VprBP drives gene silencing program in an H2AT120p-dependent manner.
Conclusions:
Our results establish VprBP-mediated H2AT120p as a key epigenetic signal for melanomagenesis and suggest the therapeutic potential of targeting VprBP kinase activity for effective melanoma treatment.
Insights
The VprBP kinase phosphorylates histone H2A at T120, driving gene silencing in melanoma. Inhibiting VprBP kinase activity shows therapeutic potential for melanoma treatment.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Melanoma, an aggressive skin cancer, involves epigenetic dysregulation.
- VprBP (DCAF1) is a kinase linked to tumor suppressor gene downregulation in colon and prostate cancers.
- VprBP's role in melanoma pathogenesis was previously unknown.
Purpose of the Study:
- To investigate the role of VprBP in melanoma development.
- To determine if VprBP's kinase activity is essential for melanoma growth.
Main Methods:
- Assessed VprBP expression and histone H2A phosphorylation (H2AT120p) in melanoma cells.
- Utilized VprBP knockdown and inhibitors in xenograft models.
- Employed gene silencing assays with VprBP wild type and kinase-dead mutants.
Main Results:
- VprBP is highly expressed in melanoma, phosphorylating H2A at T120 to silence growth regulatory genes.
- VprBP-mediated H2AT120p is crucial for melanoma cell growth, as inhibition mitigates tumor progression.
- VprBP drives gene silencing in an H2AT120p-dependent manner.
Conclusions:
- VprBP-mediated H2AT120p is a key epigenetic driver of melanoma.
- Targeting VprBP kinase activity presents a potential therapeutic strategy for melanoma.
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