Involvement of lnc162 on sensitivity to DNA demethylating agents

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02704
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Ushijima Toshikazu 国立研究開発法人国立がん研究センター, 研究所, 分野長 (90232818)
• Co-Investigator(Kenkyū-buntansha): 服部 奈緒子 国立研究開発法人国立がん研究センター, 研究所, 研究員 (30611090)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: DNA脱メチル化治療 / 効果予測マーカー / lncRNA

Outline of Final Research Achievements

DNA demethylation therapy is now expanding from hematological tumors to solid tumors. Previously, we have identified a long noncoding RNA, linc00162 (lnc162), as highly
and frequently expressed in gastric cancer cell lines sensitive to 5-aza-2′-deoxycytidine (5-aza-dC). Here, we aimed to reveal the molecular mechanisms how lnc162 is involved in 5-aza-dC sensitivity and the function of lnc162 in other solid tumors. In vivo experiments showed that lnc162
overexpression increased the sensitivity. Mechanistically, lnc162 interacted with an RNA splicing protein, HNRNPH1, and decreased splicing of an anti-apoptotic splicing variant, BCL-XL. In liposarcomas cell lines, lnc162 expression was induced by the treatment of 5-aza-dC, meaning that the involvement of lnc162 in 5-aza-dC sensitivity is universally applicable to solid tumors. lnc162 may have translational value to predict patients who will respond to 5-aza-dC. We have published these findings as an original paper.

Free Research Field

分子生物学、エピジェネティクス

Academic Significance and Societal Importance of the Research Achievements

本研究によって、固形腫瘍へのDNA脱メチル化剤治療の効果予測マーカーであるlnc162が同定された。また、今回明らかとなった作用機序を考慮すると、lnc162を標的とすることによって、DNA脱メチル化剤を増強する治療戦略の開発につながる可能性もあることが示された。この研究成果によって、停滞している固形腫瘍へのDNA脱メチル化剤治療が促進すると考えられる。