Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, 110122, China.
Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, China.
Cell Death Differ. 2019 Oct;26(10):1905-1917. doi: 10.1038/s41418-018-0259-4. Epub 2019 Jan 15.
The expression and activity of CCAAT/enhancer-binding protein α (C/EBPα) are involved in sumoylation modification, which is critical to divert normal cells from differentiation to proliferation. However, the role and underlying mechanism of C/EBPα in cancer is poorly understood. Human MORC2 (microrchidia family CW-type zinc-finger 2), is a member of the MORC proteins family containing a CW-type zinc-finger domain. Here, we found that MORC2 interacted with TE-III domain of C/EBPα, and the overexpression of MORC2 promoted wild-type C/EBPα sumoylation and its subsequent degradation, which didn't significantly observe in mutant C/EBPα-K161R. Furthermore, the overexpression of MORC2 inhibited C/EBPα-mediated C2C12 cell differentiation to maintain cell cycle progression. Moreover, the striking correlation between the decreased C/EBPα expression and the increased MORC2 expression was also observed in the poor differentiation status of gastric cancer tissues. Most notably, the high expression of MORC2 is correlated with an aggressive phenotype of clinical gastric cancer and shorter overall survival of patients. Taken together, our findings demonstrated that MORC2 expression regulated C/EBPα-mediated the axis of differentiation/proliferation via sumoylation modification, and affected its protein stability, causing cell proliferation and tumorigenesis.
CCAAT/增强子结合蛋白α（C/EBPα）的表达和活性涉及到 SUMO 化修饰，这对于使正常细胞从分化转向增殖至关重要。然而，C/EBPα 在癌症中的作用和潜在机制尚不清楚。人类 MORC2（微幼虫家族 CW 型锌指 2）是 MORC 蛋白家族的一员，含有 CW 型锌指结构域。在这里，我们发现 MORC2 与 C/EBPα 的 TE-III 结构域相互作用，并且过表达 MORC2 促进野生型 C/EBPα 的 SUMO 化及其随后的降解，而在突变型 C/EBPα-K161R 中则没有明显观察到。此外，过表达 MORC2 抑制了 C/EBPα 介导的 C2C12 细胞分化，从而维持细胞周期的进行。此外，在胃癌组织分化不良状态下，还观察到 C/EBPα 表达减少与 MORC2 表达增加之间的显著相关性。最值得注意的是，MORC2 的高表达与临床胃癌侵袭性表型和患者总生存期缩短相关。综上所述，我们的研究结果表明，MORC2 的表达通过 SUMO 化修饰调节 C/EBPα 介导的分化/增殖轴，影响其蛋白稳定性，导致细胞增殖和肿瘤发生。
