染色质蛋白激酶VRK1的生物学功能及其在癌症靶向治疗中的意义

The biological functions of chromatin protein kinase VRK1 and the clinical implications as a target in cancer therapy

牛痘相关激酶1(vaccinia-related kinase 1,VRK1)是一种核染色质丝苏氨酸蛋白激酶,在癌症中不发生基因突变,但在很多类型的肿瘤中表达上调并与不良预后相关。在细胞核内,VRK1可以磷酸化几种转录因子、组蛋白和涉及DNA损伤反应途径的蛋白质,还可以参与转录过程中组蛋白的乙酰化修饰,调节细胞周期、有丝分裂等过程促进细胞增殖,并且在DNA损伤修复中发挥至关重要的作用。在DNA损伤修复反应中,VRK1调控组蛋白乙酰化,介导DNA损伤反应的触发,进一步参与非同源末端连接DNA修复途径,还可以调控p53相关的DNA损伤修复过程。基于VRK1的以上生物学功能,癌组织中VRK1的高表达可以促进肿瘤细胞增殖、转移以及参与肿瘤细胞DNA修复过程。在癌症靶向治疗研究中,VRK1可以作为癌症合成致死性策略的选择靶点用于多种癌症的防治。

VRK1(vaccinia-related kinase 1)is a serine-threonine protein kinase generally distributed around nuclear chromatin.It usually doesn't mutate in cancer,but is upregulated in many tumors,which is associated with poor prognosis.In the nucleus,VRK1 can phosphorylate several transcription factors,histones and proteins involved in the DNA damage response,and also participate in acetylation modification of histones during gene transcription.Functionally,VRK1 may regulate cell cycle,mitosis and other processes to promote cell proliferation,and play a critical role in DNA damage repair.In the process of DNA damage,VRK1 regulates histone acetylation to trigger the DNA damage response,and further participates in the nonhomologous end-joining DNA repair pathway,and is also related to the p53-mediated DNA damage repair response.Based on the above functions of VRK1,elevated expression of VRK1 in cancer tissues may promote tumor cell proliferation,metastasis,and remain genomic stability.In the studies aiming at cancer therapeutic target,VRK1 can be used as a selective target for cancer synthetic lethal strategies in the prevention and treatment of various cancers.