RNA methylation of T-UCRs regulates colon cancer progression

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08007
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokushima
• Principal Investigator: KUWANO Yuki 徳島大学, 大学院医歯薬学研究部(医学域), 講師 (00563454)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: RNA修飾 / RNAメチル化 / 選択的スプライシング / 大腸がん / 超保存領域

Outline of Final Research Achievements

RNA methylation at adenosine N6 (m6A) is one of the most common RNA modifications which affects RNA processing, transport, and translation. Ultraconserved regions (UCRs) are 481 genomic sequences with 100% identity across humans, rats, and mice. Increasing evidence suggests that non-coding RNAs transcribed from UCRs are involved in various diseases, especially cancers.
Overexpression of T-UCR in colon cancer cells promoted cell proliferation by changing the expression of G2/M-related cell cycle regulators. m6A methylation of T-UCR was upregulated in cancer cells, compared with that of normal colon epithelial cells. We found m6A methylated RNA preferentially bound to several cancer-related RNA-binding proteins. Inhibition of m6A methylation decreased T-UCR levels and cell growth of colon cancer cells. These results suggest that m6A modification plays a pathogenic role in cell proliferation of cancer cells and may become a potential biomarker and therapeutic target for colon cancer.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究で着目したT-UCRは中途ストップコドンを持ちタンパク質には翻訳されず、 従来速やかに分解されるRNAであるため、T-UCRの蓄積は疾患特異的なバイオマーカーと成り得る。
本研究成果によって、T-UCRががん細胞核に蓄積するメカニズムの一端として、がん細胞に特徴的なm6A RNAメチル化修飾パターンと関連するRNA結合タンパク質を見出した。今後、がん細胞のみで認められるメチル化修飾配列を標的とした、正規タンパク質発現に影響を与えない、新しいコンセプトの核酸医薬の開発に繋がる可能性がある。