VprBP regulates osteoclast differentiation via histone H2A phosphorylation
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ABSTRACT:
PROVIDER: PRJNA1152008 | ENA |
REPOSITORIES: ENA
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Project description:Bone remodeling is a continuous and balanced process which relies on the dynamic equilibrium between osteoclastic bone resorption and osteoblastic bone formation. During osteoclast differentiation, pro-osteoclastogenic and anti-osteoclastogenic genes are selectively targeted by positive and negative transcription regulators, respectively. VprBP, also known as DCAF1, is a recently identified kinase and plays an important role in driving epigenetic gene silencing and oncogenic transformation. However, nothing is currently known about a possible involvement of VprBP in signaling pathways that regulates other cellular processes. Here, we demonstrate that VprBP stimulates RANKL-induced osteoclast differentiation by attenuating the expression of anti-osteoclastogenic genes through phosphorylating histone H2A at threonine 120 (H2AT120p). H2AT120p is critical for VprBP function, because abrogating VprBP kinase activity toward H2AT120 significantly attenuates the differentiation of osteoclast precursor cells (OCPs) into mature osteoclasts. Consistent with this notion, our in vivo studies established the importance of VprBP-mediated H2AT120p in low bone mass phenotypes and osteoporosis caused by overactive osteoclasts. Together, our data reveal a previously unrecognized function of VprBP in supporting osteoclast differentiation and the molecular mechanism underlying its action as a negative regulator of anti-osteoclastogenic genes.
2025-01-28 | GSE275603 | GEO
Project description:VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation
| PRJNA961784 | ENA
Project description: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 VprBP inhibitor B32B3 impairs colonic tumor growth by blocking H2AT120p and reactivating 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.
2021-10-06 | GSE180282 | GEO
Project description:DCAF1, also known as VprBP, is a recently identified atypical 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. 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. Here we demonstrate that DCAF1 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 other types of cancers, DCAF1 acts to induce gene silencing program dependently of H2AT120 phosphorylation (H2AT120p). The significance of DCAF1-mediated H2AT120p is further underscored by the fact that DCAF1 knockdown- or DCAF1 inhibitor-induced lockage of H2AT120p mitigates melanoma tumor growth in xenograft models. Collectively, our results establish DCAF1-mediated H2AT120p as a key epigenetic signal for melanomagenesis and suggest the therapeutic potential of targeting DCAF1 kinase activity for effective melanoma treatment.
2023-05-05 | GSE230573 | GEO
Project description:VprBP directs epigenetic gene silencing through H2A phosphorylation in colon cancer
| PRJNA747687 | ENA
Project description:Our recent work has shown that VprBP is overexpressed in colon cancer and phosphorylates histone H2AT120 to drive epigenetic gene inactivation and oncogenic transformation. We have extended these observations by investigating whether VprBP also phosphorylates non-histone proteins as an additional mechanism linking its kinase activity to colon cancer development. We now demonstrate that VprBP directly phosphorylates EZH2 at T367 to augment its nuclear stabilization and enzymatic activity in colon cancer cells. Consistent with this mechanistic role, VprBP-mediated EZH2 phosphorylation leads to elevated levels of H3K27me3 and altered expression of growth regulatory genes in cancer cells. Furthermore, our preclinical studies using organoid and xenograft models revealed that EZH2 requires phosphorylation for its oncogenic function, which may have therapeutic implications for gene reactivation in colon cancer cells. Together, our data define a new mechanism underlying VprBP-driven colonic tumorigenesis by linking VprBP-mediated EZH2 phosphorylation to EZH2 stability that is crucial for establishing H3K27me3 and gene silencing program.
2023-03-28 | GSE192489 | GEO
Project description:Vpr binding protein (VprBP), also known as DDB1- and CUL4-associated factor1 (DCAF1), is a recently identified atypical 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. Melanoma is the most aggressive form of skin cancer arising from pigment-producing melanocytes and is often associated with the dysregulation of epigenetic factors targeting histones. Here, we demonstrate that VprBP is highly expressed and phosphorylates threonine 120 (T120) on histone H2A to drive the transcriptional inactivation of growth-regulatory genes in melanoma cells. As is the case for its epigenetic function in other types of cancers, VprBP acts to induce a gene silencing program dependent on 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. Collectively, 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.
| S-EPMC10526264 | biostudies-literature
Project description:It is well known that deregulation of chromatin modifiers, such as histone acetylases and methylases, causes malignancies. However, the possible role of histone phosphorylation in carcinogenesis has not yet been elucidated. Here, we found that histone phosphorylation by itself can be the causal event in carcinogenesis. First, we found that histone H2A T120 is phosphorylated in human cancer cell lines and proved that this phosphorylation is catalyzed by hVRK1. By knocking down VRK1, cyclin D1 was found to be downregulated by loss of H2A T120 phosphorylation and increased H2A K119 ubiquitylation of its promoter region, resulting in impaired cell growth. In human cancer tissues, we found that histone H2A is hyperphosphorylated, with upregulated cyclin D1. Mechanistically, histone H2A T120 phosphorylation and histone H2A K119 ubiquitylation, which repress transcription, are mutually inhibitory, suggesting that histone phosphorylation indirectly activates chromatin. Furthermore, mutated H2A T120D, which mimics phosphorylation, causes elevated H3K4 methylation in the same nucleosome. Subsequently, H3K4R, which functionally mimics H3K4 methylation, increases H3 S10 phosphorylation in the same nucleosome. Finally, both VRK1 and the H2A T120D mutant histone transformed NIH/3T3 cells. This suggests that histone H2A T120 phosphorylation by hVRK1 causes inappropriate gene and protein expression, including upregulated cyclin D1, resulting in carcinogenesis.
2016-10-07 | GSE84527 | GEO
Project description:It is well known that deregulation of chromatin modifiers, such as histone acetylases and methylases, causes malignancies. However, the possible role of histone phosphorylation in carcinogenesis has not yet been elucidated. Here, we found that histone phosphorylation by itself can be the causal event in carcinogenesis. First, we found that histone H2A T120 is phosphorylated in human cancer cell lines and proved that this phosphorylation is catalyzed by hVRK1. By knocking down VRK1, cyclin D1 was found to be downregulated by loss of H2A T120 phosphorylation and increased H2A K119 ubiquitylation of its promoter region, resulting in impaired cell growth. In human cancer tissues, we found that histone H2A is hyperphosphorylated, with upregulated cyclin D1. Mechanistically, histone H2A T120 phosphorylation and histone H2A K119 ubiquitylation, which repress transcription, are mutually inhibitory, suggesting that histone phosphorylation indirectly activates chromatin. Furthermore, mutated H2A T120D, which mimics phosphorylation, causes elevated H3K4 methylation in the same nucleosome. Subsequently, H3K4R, which functionally mimics H3K4 methylation, increases H3 S10 phosphorylation in the same nucleosome. Finally, both VRK1 and the H2A T120D mutant histone transformed NIH/3T3 cells. This suggests that histone H2A T120 phosphorylation by hVRK1 causes inappropriate gene and protein expression, including upregulated cyclin D1, resulting in carcinogenesis.
2016-10-07 | GSE84583 | GEO
Project description: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.
| S-EPMC8486565 | biostudies-literature