Suppressor of Variegation 3-9 Homolog 2, a Novel Binding Protein of Translationally Controlled Tumor Protein, Regulates Cancer Cell Proliferation
Suppressor of Variegation 3-9 Homolog 2, a Novel Binding Protein of Translationally Controlled Tumor Protein, Regulates Cancer Cell Proliferation
复制标题
DOI：
10.4062/biomolther.2019.021
复制
发表时间：
2019-03-01
影响因子：
3.7
通讯作者：
Yoon, Kyungsil
中科院分区：
文献类型：
--
作者：
Kim, A-Reum;Sung, Jee Young;Yoon, Kyungsil
杂色抑制因子3-9同源物2（SUV 39 H2）甲基化组蛋白H3的赖氨酸9残基并诱导异染色质形成，导致靶基因的转录抑制或沉默。SUV 39 H1和SUV 39 H2在胚胎发育中具有作用，并且SUV 39 H1显示出抑制与Rb相关的细胞周期进展。然而，人SUV 39 H2的功能尚未被广泛研究。我们观察到SUV 39 H2的强制表达通过诱导G（1）细胞周期阻滞而降低细胞增殖。此外，SUV 39 H2通过泛素-蛋白酶体途径降解。利用酵母双杂交筛选技术研究了SUV 39 H2的降解机制和功能，并鉴定了一种与SUV 39 H2相互作用的抑制性肿瘤蛋白（TCTP）。相互作用区域的作图表明，全长SUV 39 H2的N-末端60个氨基酸（aa）和TCTP的C-末端（120-172 aa）对于结合是关键的。通过免疫共沉淀和免疫荧光染色共定位进一步证实了SUV 39 H2和TCTP的相互作用。此外，通过RNAi去除TCTP导致SUV 39 H2蛋白上调，而TCTP过表达降低SUV 39 H2蛋白水平。TCTP耗尽后，SUV 39 H2蛋白的半衰期显著延长。这些结果清楚地表明，TCTP负调控SUV 39 H2的表达后，抑制。此外，SUV 39 H2在TCTP敲低细胞中诱导凋亡性细胞死亡。综上所述，我们鉴定了SUV 39 H2作为TCTP的新靶蛋白，并证明SUV 39 H2调节肺癌细胞的细胞增殖。
Suppressor of Variegation 3-9 Homolog 2 (SUV39H2) methylates the lysine 9 residue of histone H3 and induces heterochromatin formation, resulting in transcriptional repression or silencing of target genes. SUV39H1 and SUV39H2 have a role in embryonic development, and SUV39H1 was shown to suppress cell cycle progression associated with Rb. However, the function of human SUV39H2 has not been extensively studied. We observed that forced expression of SUV39H2 decreased cell proliferation by inducing G(1) cell cycle arrest. In addition, SUV39H2 was degraded through the ubiquitin-proteasomal pathway. Using yeast two-hybrid screening to address the degradation mechanism and function of SUV39H2, we identified translationally controlled tumor protein (TCTP) as an SUV39H2-interacting molecule. Mapping of the interacting regions indicated that the N-terminal 60 amino acids (aa) of full-length SUV39H2 and the C-terminus of TCTP (120-172 aa) were critical for binding. The interaction of SUV39H2 and TCTP was further confirmed by co-immunoprecipitation and immunofluorescence staining for colocalization. Moreover, depletion of TCTP by RNAi led to up-regulation of SUV39H2 protein, while TCTP overexpression reduced SUV39H2 protein level. The half-life of SUV39H2 protein was significantly extended upon TCTP depletion. These results clearly indicate that TCTP negatively regulates the expression of SUV39H2 post-translationally. Furthermore, SUV39H2 induced apoptotic cell death in TCTP-knock-down cells. Taken together, we identified SUV39H2, as a novel target protein of TCTP and demonstrated that SUV39H2 regulates cell proliferation of lung cancer cells.