Kim Eun Ji, Park Mi Kyung, Byun Hyun Jung, Kang Gyeoung Jin, Yu Lu, Kim Hyun Ji, Shim Jae Gal, Lee Ho, Lee Chang Hoon
College of Pharmacy, Dongguk University-Seoul, 04620, Seoul, South Korea.
National Cancer Center, Goyang, 10408, South Korea.
Oncotarget. 2018 May 1;9(33):22915-22928. doi: 10.18632/oncotarget.25145.
Lung cancer is a fatal disease with a high mortality rate. The perinuclear reorganization of keratin 8 (K8) is an important biochemical phenomenon reflecting changes in the physical properties of metastatic cancer. However, there is not much of information about the regulatory molecules involved in phosphorylation and perinuclear reorganization of K8. In this study, we investigated the role and molecular mechanisms of YdjC chitooligosaccha- ride deacetylase homolog (YDJC) in sphingosylphosphorylcholine (SPC)-induced phosphorylation and reorganization of K8, and migration and invasion (SPC-induced events). SPC induced expression of YDJC in a dose- and time-dependent manner. Gene silencing of YDJC suppressed SPC-induced events. YDJC overexpression induced the SPC-induced events. YDJC deacetylase dominant negative mutant (YDJCD13A) did not induce SPC-induced events. YDJC siRNA reduced ERK activation and overexpression of YDJC induced ERK activation. The siRNA of ERK1 or ERK2 suppressed YDJC-induced phosphorylation and reorganization of K8, and migration and invasion. Co-immunoprecipitation revealed that YDJC binds to CDC16. Interestingly, CDC16 siRNA induced SPC-induced events. Overexpression of CDC16 blocked SPC-induced events. KMPLOT analysis based on public microarray data revealed the poor prognosis of lung cancer patients with high expression of YDJC compared with patients with low expression of YDJC. The collective results indicate that YDJC is involved in SPC-induced events in A549 lung cancer cells by interacting with CDC16. YDJC overexpression might be involved in the progression of lung cancer. These results also suggest that suppression of YDJC or boosting of CDC16 interaction with YDJC might be a novel way to prevent progression of lung cancer.
肺癌是一种死亡率很高的致命疾病。角蛋白8（K8）的核周重排是反映转移性癌症物理性质变化的重要生化现象。然而，关于参与K8磷酸化和核周重排的调控分子的信息并不多。在本研究中，我们研究了YdjC壳寡糖脱乙酰酶同源物（YDJC）在鞘氨醇磷酸胆碱（SPC）诱导的K8磷酸化和重排以及迁移和侵袭（SPC诱导事件）中的作用和分子机制。SPC以剂量和时间依赖性方式诱导YDJC的表达。YDJC的基因沉默抑制了SPC诱导的事件。YDJC的过表达诱导了SPC诱导的事件。YDJC脱乙酰酶显性负突变体（YDJCD13A）未诱导SPC诱导的事件。YDJC siRNA降低了ERK激活，而YDJC的过表达诱导了ERK激活。ERK1或ERK2的siRNA抑制了YDJC诱导的K8磷酸化和重排以及迁移和侵袭。免疫共沉淀显示YDJC与CDC16结合。有趣的是，CDC16 siRNA诱导了SPC诱导的事件。CDC16的过表达阻断了SPC诱导的事件。基于公共微阵列数据的KMPLOT分析显示，与YDJC低表达的肺癌患者相比，YDJC高表达的肺癌患者预后较差。总体结果表明，YDJC通过与CDC16相互作用参与A549肺癌细胞中SPC诱导的事件。YDJC的过表达可能参与肺癌的进展。这些结果还表明，抑制YDJC或增强CDC16与YDJC的相互作用可能是预防肺癌进展的新方法。
