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VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation

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 th...

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Autores principales: Shin, Yonghwan, Kim, Sungmin, Liang, Gangning, Ulmer, Tobias S, An, Woojin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10246234/
https://www.ncbi.nlm.nih.gov/pubmed/37293029
http://dx.doi.org/10.21203/rs.3.rs-2950076/v2
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author Shin, Yonghwan
Kim, Sungmin
Liang, Gangning
Ulmer, Tobias S
An, Woojin
author_facet Shin, Yonghwan
Kim, Sungmin
Liang, Gangning
Ulmer, Tobias S
An, Woojin
author_sort Shin, Yonghwan
collection PubMed
description 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.
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spelling pubmed-102462342023-06-08 VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation Shin, Yonghwan Kim, Sungmin Liang, Gangning Ulmer, Tobias S An, Woojin Res Sq Article 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. American Journal Experts 2023-07-12 /pmc/articles/PMC10246234/ /pubmed/37293029 http://dx.doi.org/10.21203/rs.3.rs-2950076/v2 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Shin, Yonghwan
Kim, Sungmin
Liang, Gangning
Ulmer, Tobias S
An, Woojin
VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation
title VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation
title_full VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation
title_fullStr VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation
title_full_unstemmed VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation
title_short VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation
title_sort vprbp/dcaf1 triggers melanomagenic gene silencing through histone h2a phosphorylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10246234/
https://www.ncbi.nlm.nih.gov/pubmed/37293029
http://dx.doi.org/10.21203/rs.3.rs-2950076/v2
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