Department of Human Anatomy, Histology and Embryology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, 100191, China.
Department Bioinformatics, Peking University Health Science Center, Beijing, 100191, China.
Cancer Lett. 2018 Jul 1;425:78-87. doi: 10.1016/j.canlet.2018.03.038. Epub 2018 Mar 29.
Slug is a fast-turnover transcription factor critical for controlling cell fate and cancer cell invasion and metastasis. The stability of Slug is important and maintained by diverse mechanisms. In this study, we presented a paradigm of this activity by identifying long noncoding RNA (lncRNA) small nucleolar RNA host gene 15 (SNHG15) that binds to and stabilizes Slug in colon cancer cells. LncRNA SNHG15 transcription is upregulated in a variety of human cancers according to The Cancer Genome Atlas. Here, ectopic expression of SNHG15 promoted colon cancer cell migration in vitro, accelerated xenografted tumor growth in vivo, and elevated levels of SNHG15 were associated with poor prognosis for colon cancer patients. Mechanistically, SNHG15 maintains Slug stability in living cells by impeding its ubiquitination and degradation through interaction with the zinc finger domain of Slug. These findings revealed a novel mechanism underlying the control of Slug stability by demonstrating that oncogenic lncRNA SNHG15 interacts with and blocks Slug degradation via the ubiquitin-proteasome system.
Slug 是一种快速周转的转录因子，对控制细胞命运和癌细胞侵袭转移至关重要。Slug 的稳定性很重要，并通过多种机制来维持。在这项研究中，我们通过鉴定长链非编码 RNA（lncRNA）小核仁 RNA 宿主基因 15（SNHG15），发现了 Slug 在结肠癌细胞中结合并稳定 Slug 的这种活性的范例。根据癌症基因组图谱，lncRNA SNHG15 的转录在多种人类癌症中上调。在这里，SNHG15 的异位表达促进了体外结肠癌细胞的迁移，加速了体内异种移植肿瘤的生长，并且 SNHG15 水平的升高与结肠癌症患者的预后不良相关。从机制上讲，SNHG15 通过与 Slug 的锌指结构域相互作用来阻碍其泛素化和降解，从而在活细胞中维持 Slug 的稳定性。这些发现揭示了一种新的 Slug 稳定性控制机制，表明致癌 lncRNA SNHG15 通过泛素-蛋白酶体系统相互作用并阻止 Slug 降解。
