Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Oncogene. 2019 Jun;38(26):5281-5293. doi: 10.1038/s41388-019-0792-8. Epub 2019 Mar 26.
DNA demethylation therapy is now expanding from hematological tumors to solid tumors. To exploit its maximum efficacy, long-term treatment is needed, and stratification of sensitive patients is critically important. Here, we identified a long non-coding RNA, LINC00162, as highly and frequently expressed in gastric cancer cell lines sensitive to 5-aza-2'-deoxycytidine (5-aza-dC). Knockdown of LINC00162 decreased the sensitivity while its overexpression increased the sensitivity. In vivo experiments also showed that LINC00162 overexpression increased the sensitivity. LINC00162 enhanced cell cycle arrest and apoptosis induced by 5-aza-dC, but did not affect its DNA demethylation effect. Mechanistically, LINC00162 interacted with an RNA splicing protein, HNRNPH1, and decreased splicing of an anti-apoptotic splicing variant, BCL-XL. LINC00162 may have translational value to predict patients who will respond to 5-aza-dC.
DNA 去甲基化治疗目前正在从血液肿瘤扩展到实体肿瘤。为了发挥其最大疗效，需要长期治疗，对敏感患者进行分层至关重要。在这里，我们鉴定了一种长非编码 RNA，LINC00162，在对 5-氮杂-2'-脱氧胞苷（5-aza-dC）敏感的胃癌细胞系中高度且频繁表达。LINC00162 的敲低降低了敏感性，而过表达则增加了敏感性。体内实验也表明，LINC00162 的过表达增加了敏感性。LINC00162 增强了 5-aza-dC 诱导的细胞周期停滞和细胞凋亡，但不影响其 DNA 去甲基化作用。机制上，LINC00162 与 RNA 剪接蛋白 HNRNPH1 相互作用，减少抗凋亡剪接变体 BCL-XL 的剪接。LINC00162 可能具有预测对 5-aza-dC 有反应的患者的翻译价值。
