VprBP directs epigenetic gene silencing through histone H2A phosphorylation in colon cancer.
Mol Oncol
; 15(10): 2801-2817, 2021 10.
Article
em En
| MEDLINE
| ID: mdl-34312968
ABSTRACT
Histone modification is aberrantly regulated in cancer and generates an unbalanced state of gene transcription. VprBP, a recently identified kinase, phosphorylates histone H2A on threonine 120 (T120) and is involved in oncogenic transcriptional dysregulation; however, its specific role in colon cancer is undefined. Here, we show that VprBP is overexpressed in colon cancer and directly contributes to epigenetic gene silencing and cancer pathogenesis. Mechanistically, the observed function of VprBP is mediated through H2AT120 phosphorylation (H2AT120p)-driven transcriptional repression of growth regulatory genes, resulting in a significantly higher proliferative capacity of colon cancer cells. Our preclinical studies using organoid and xenograft models demonstrate that treatment with the VprBP inhibitor B32B3 impairs colonic tumor growth by blocking H2AT120p and reactivating a transcriptional program resembling that of normal cells. Collectively, our work describes VprBP as a master kinase contributing to the development and progression of colon cancer, making it a new molecular target for novel therapeutic strategies.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Histonas
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Proteínas Serina-Treonina Quinases
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Neoplasias do Colo
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Ubiquitina-Proteína Ligases
Limite:
Humans
Idioma:
En
Revista:
Mol Oncol
Ano de publicação:
2021
Tipo de documento:
Article