Affiliation:
1. University of Southern California
Abstract
Abstract
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.
Publisher
Research Square Platform LLC
Reference51 articles.
1. Cytoplasmic retention of HIV-1 regulatory protein Vpr by protein-protein interaction with a novel human cytoplasmic protein VprBP;Zhang S;Gene,2001
2. VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation;Huang J;Oncogene,2008
3. HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase;Rouzic E;Cell Cycle,2007
4. Human immunodeficiency virus type 1 Vpr-binding protein VprBP, a WD40 protein associated with the DDB1-CUL4 E3 ubiquitin ligase, is essential for DNA replication and embryonic development;McCall CM;Mol Cell Biol,2008
5. CRL4(DCAF1/VprBP) E3 ubiquitin ligase controls ribosome biogenesis, cell proliferation, and development;Han XR;Sci Adv.,2020