Shin Yonghwan, Kim Sungmin, Liang Gangning, Ulmer Tobias S, An Woojin
Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
Biomedicines. 2023 Sep 17;11(9):2552. doi: 10.3390/biomedicines11092552.
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.
Vpr结合蛋白（VprBP），也被称为损伤DNA结合蛋白1（DDB1）和CUL4相关因子1（DCAF1），是一种最近被鉴定出的非典型激酶，在下调肿瘤抑制基因转录以及增加结肠癌和前列腺癌风险方面发挥重要作用。黑色素瘤是源自产生色素的黑素细胞的最具侵袭性的皮肤癌形式，并且通常与靶向组蛋白的表观遗传因子失调有关。在此，我们证明VprBP在黑色素瘤细胞中高表达并使组蛋白H2A上的苏氨酸120（T120）磷酸化，以驱动生长调节基因的转录失活。正如其在其他类型癌症中的表观遗传功能一样，VprBP通过依赖H2A T120磷酸化（H2A T120p）来诱导基因沉默程序。VprBP敲低或VprBP抑制剂诱导的H2A T120p阻断减轻了异种移植模型中黑色素瘤肿瘤的生长，这一事实进一步强调了VprBP介导的H2A T120p的重要性。总体而言，我们的结果确立了VprBP介导的H2A T120p作为黑色素瘤发生的关键表观遗传信号，并提示靶向VprBP激酶活性用于有效治疗黑色素瘤的治疗潜力。
