Functional analysis and clinical application of DLEU1 in oral squamous cell carcinoma

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K19239
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Yui Hatanaka 札幌医科大学, 医学部, 研究員 (60815265)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 口腔扁平上皮がん / noncoding RNA / lncRNA / エピゲノム / がん遺伝子シグナル

Outline of Final Research Achievements

We found that DLEU1 is one of the long noncoding RNAs (lncRNAs) overexpressed in oral squamous cell carcinoma (OSCC) cells, where it exhibits oncogenic activity. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that DLEU1 knockdown induced significant changes in the levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27 acetylation (H3K27ac) in OSCC cells. DLEU1 knockdown suppressed levels of H3K4me3/ H3K27ac and expression of a number of interferon-stimulated genes (ISGs), while ectopic DLEU1 expression activated these genes. Western blot analysis and reporter assays suggested that DLEU1 upregulates ISGs through activation of JAK-STAT signaling in OSCC cells. IFITM1, one of the ISGs induced by DLUE1, was frequently overexpressed in primary OSCC tumors, and its knockdown inhibited OSCC cell proliferation, migration and invasion. Our findings suggest that DLEU1 exerts its oncogenic effects, at least in part, through activation of ISGs in OSCC cells.

Free Research Field

口腔外科学

Academic Significance and Societal Importance of the Research Achievements

口腔がんの5年生存率は約50%であり、さらなる治療標的の同定が求められている。近年、長鎖非コードRNA(lncRNA)のがんにおける役割が注目されており、研究報告数が増加している。しかし、1～2万種類存在するlncRNAの多くは、その機能が未だ不明である。これまで我々はDLEU1というlncRNAが口腔がんにおいて発現上昇し、かつ腫瘍促進的に機能することを明らかにしてきた。本研究では、DLEU1が口腔がん細胞のエピゲノム制御に関わること、DLEU1がインターフェロンシグナルを活性化すること、DLEU1によって活性化される下流標的遺伝子が腫瘍促進的に働くことを明らかにした。