Expression of vaccinia-related kinase 1 (VRK1) accelerates cell proliferation but overcomes cell adhesion mediated drug resistance (CAM-DR) in multiple myeloma

Liu, Jing; Wang, Yuchan; He, Song; Xu, Xiaohong; Huang, Yuejiao; Tang, Jie; Wu, Yong; Miao, Xiaobing; He, Yunhua; Wang, Qiru; Liang, Li; Cheng, Chun

doi:10.1080/10245332.2016.1147678

“…In the present study, it was also found that VRK1 expression was highest in both NCI-H520 and SK-MES-1 cell lines, and the cell viability of NCI-H520 and SK-MES-1 in the shVRK1 group was signifcantly lower than that in the shNC group, and SK-MES-1 in the shVRK1 group had signifcantly lower cell viability than in the shNC group. Previously, it was shown that VRK1 expression could promote cell proliferation in myeloma by regulating cell cycle-related proteins [18]. Te current study found that the inhibition of LUSC cell proliferation was due to depletion of VRK1, which induces the cell cycle arrest in the G0/G1 phase, which is also consistent with Carrion-Marchante et al [19].…”

Section: Discussionsupporting

confidence: 90%

Downregulation of VRK1 Inhibits Progression of Lung Squamous Cell Carcinoma through DNA Damage

Du

¹

,

Zhang

²

,

Zhang

³

2023

Canadian Respiratory Journal

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Background. Lung squamous cell carcinoma (LUSC) is a common malignancy. And the antitumor effect of bovine pox virus-associated kinase 1 (VRK1) is becoming a hot research topic. Methods. VRK1 expression and prognosis in LUSC were analyzed using the GEPIA database. The expression of VRK1 mRNA was detected in 25 LUSC clinical tissue samples by RT-PCR. VRK1 shRNA was transfected into LUSC NCI-H520 and SK-MES-1 cell lines to interfere with VRK1 expression, and the efficiency of VRK1 shRNA interference was detected by the western blot. The effects of VRK1 downregulation on LUSC cell viability, migration, cell cycle, and apoptosis were analyzed by the CCK8 assay, scratch assay, transwell assay, and flow cytometry. The effect of VRK1 downregulation on DNA damage response (DDR) was examined by immunofluorescence staining and western blot assays and further validated by in vivo experiments. Results. VRK1 was highly expressed in both LUSC tissues and cells. Survival analysis showed that the overall survival of LUSC patients with high VRK1 expression was significantly lower than that of LUSC patients with low VRK1 expression ( P = 0.0026 ). The expression level of the VRK1 gene was significantly higher in cancer tissues of LUSC patients than in paracancerous tissues. After transfection of VRK1 shRNA in both LUSC cells, cell activity decreased ( P < 0.001 ), migration ability started to be inhibited ( P < 0.001 ), the ratio of G0/G1 phase cells increased ( P < 0.001 ), and apoptosis rate increased ( P < 0.001 ). Immunofluorescence and western blot results showed that shVRK1 increased the level of γ-H2A.X ( P < 0.001 ) and promoted apoptosis of tumor cells ( P < 0.001 ). In addition, the results of animal experiments showed that shVRK1 had antitumor effects ( P < 0.001 ) and a combined effect with DOX ( P < 0.001 ). Conclusion. The downregulation of VRK1 significantly affected the proliferation, apoptosis, migration, and cell cycle progression of LUSC cells via DDR, suggesting that VRK1 is a suitable target for potential LUSC therapy.

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“…Our gene expression and ontology analysis predicts that VRK1 expression is associated in neuroblastoma tumors with signaling pathways involved in cell cycle regulation, DNA replication or DNA repair. VRK1 has been described as a proliferation control protein in human fibroblasts and in some cancers like head and neck or myeloma [19,29,30]. We have identified that VRK1 is associated with cell proliferation in NB tumor cells and that it is an essential gene controlling cell division in these tumors.…”

Section: Discussionmentioning

confidence: 84%

Identification of VRK1 as a New Neuroblastoma Tumor Progression Marker Regulating Cell Proliferation

Colmenero-Repiso

¹

,

Gómez-Muñoz

²

,

Rodríguez-Prieto

³

et al. 2020

Cancers

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Neuroblastoma (NB) is one of the most common pediatric cancers and presents a poor survival rate in affected children. Current pretreatment risk assessment relies on a few known molecular parameters, like the amplification of the oncogene MYCN. However, a better molecular knowledge about the aggressive progression of the disease is needed to provide new therapeutical targets and prognostic markers and to improve patients’ outcomes. The human protein kinase VRK1 phosphorylates various signaling molecules and transcription factors to regulate cell cycle progression and other processes in physiological and pathological situations. Using neuroblastoma tumor expression data, tissue microarrays from fresh human samples and patient-derived xenografts (PDXs), we have determined that VRK1 kinase expression stratifies patients according to tumor aggressiveness and survival, allowing the identification of patients with worse outcome among intermediate risk. VRK1 associates with cell cycle signaling pathways in NB and its downregulation abrogates cell proliferation in vitro and in vivo. Through the analysis of ChIP-seq and methylation data from NB tumors, we show that VRK1 is a MYCN gene target, however VRK1 correlates with NB aggressiveness independently of MYCN gene amplification, synergizing with the oncogene to drive NB progression. Our study also suggests that VRK1 inhibition may constitute a novel cell-cycle-targeted strategy for anticancer therapy in neuroblastoma.

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“…The VRK1 protein has characteristics that make it distinct and candidate for development of highly specific inhibitors [ 13 ], one of which has been recently developed [ 15 , 16 ]. VRK1 has been associated with the control of cell proliferation [ 17 ] and mitosis [ 18 , 19 ], and is expressed at high levels in proliferating and tumor cells [ 17 , 20 ], which is an indicator of a poorer prognosis in many tumor types [ 21 – 25 ]. VRK1 is also necessary to maintain genomic stability and its loss facilitates DNA damage by a defective DNA damage response [ 20 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

The pattern of histone H3 epigenetic posttranslational modifications is regulated by the VRK1 chromatin kinase

Monte-Serrano,

Morejón-García,

Campillo-Marcos

et al. 2023

Epigenetics & Chromatin

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Background Dynamic chromatin remodeling is associated with changes in the epigenetic pattern of histone acetylations and methylations required for processes based on dynamic chromatin remodeling and implicated in different nuclear functions. These histone epigenetic modifications need to be coordinated, a role that may be mediated by chromatin kinases such as VRK1, which phosphorylates histones H3 and H2A. Methods The effect of VRK1 depletion and VRK1 inhibitor, VRK-IN-1, on the acetylation and methylation of histone H3 in K4, K9 and K27 was determined under different conditions, arrested or proliferating cells, in A549 lung adenocarcinoma and U2OS osteosarcoma cells. Results Chromatin organization is determined by the phosphorylation pattern of histones mediated by different types of enzymes. We have studied how the VRK1 chromatin kinase can alter the epigenetic posttranslational modifications of histones by using siRNA, a specific inhibitor of this kinase (VRK-IN-1), and of histone acetyl and methyl transferases, as well as histone deacetylase and demethylase. Loss of VRK1 implicated a switch in the state of H3K9 posttranslational modifications. VRK1 depletion/inhibition causes a loss of H3K9 acetylation and facilitates its methylation. This effect is similar to that of the KAT inhibitor C646, and to KDM inhibitors as iadademstat (ORY-1001) or JMJD2 inhibitor. Alternatively, HDAC inhibitors (selisistat, panobinostat, vorinostat) and KMT inhibitors (tazemetostat, chaetocin) have the opposite effect of VRK1 depletion or inhibition, and cause increase of H3K9ac and a decrease of H3K9me3. VRK1 stably interacts with members of these four enzyme families. However, VRK1 can only play a role on these epigenetic modifications by indirect mechanisms in which these epigenetic enzymes are likely targets to be regulated and coordinated by VRK1. Conclusions The chromatin kinase VRK1 regulates the epigenetic patterns of histone H3 acetylation and methylation in lysines 4, 9 and 27. VRK1 is a master regulator of chromatin organization associated with its specific functions, such as transcription or DNA repair.

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Expression of vaccinia-related kinase 1 (VRK1) accelerates cell proliferation but overcomes cell adhesion mediated drug resistance (CAM-DR) in multiple myeloma

Abstract: Our data supports a role for VRK1 in MM cell proliferation, adhesion, and drug resistance, and it may pave the way for a novel therapeutic approach for CAM-DR in MM.

Cited by 7 publications

References 38 publications

Downregulation of VRK1 Inhibits Progression of Lung Squamous Cell Carcinoma through DNA Damage

Downregulation of VRK1 Inhibits Progression of Lung Squamous Cell Carcinoma through DNA Damage

Identification of VRK1 as a New Neuroblastoma Tumor Progression Marker Regulating Cell Proliferation

The pattern of histone H3 epigenetic posttranslational modifications is regulated by the VRK1 chromatin kinase

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