The regulation mechanism of KLF5 and CCAT1 gene expression via three-dimensional genome structure

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16541
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Osaka University
• Principal Investigator: Yokoyama Yuki 大阪大学, 医学系研究科, 助教 (60615714)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 三次元ゲノム構造 / KLF5 / CCAT1 / ノンコーディングRNA

Outline of Final Research Achievements

Kruppel-like factor 5 (KLF5) is a zinc finger transcription factor whose expression is increased in specific cancer types, such as gastrointestinal cancer and squamous carcinoma. Colon Cancer Associated Transcript 1 (CCAT1) is a long noncoding RNA that was initially found to be increased in colorectal cancer (CRC), and it is reported that high CCAT1 expression is associated with poor prognosis in CRC patients. In this study, we found that KLF5 and CCAT1 expression was correlated each other in CRC clinical samples. Furthermore, we showed that KLF5 protein bound to the KLF5 gene promoter, enhancer and CCAT1 gene transcription start site together with other co-factors. Our data propose the mechanistic insight that the KLF5 protein constructs the core regulatory circuitry with co-factors in the three-dimensional genome structure and coordinately regulates KLF5 and CCAT1 expression in CRC.

Free Research Field

癌、エピジェネティクス、分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究で対象としたKLF5遺伝子、CCAT1遺伝子はいずれも大腸癌を始めとした特定の癌種において過剰発現が報告されており、癌幹細胞性との関連も示唆されているため、有力な治療標的である。本研究で明らかとしたKLF5タンパクが三次元ゲノム構造の構築に関与し、KLF5, CCAT1遺伝子の協調的な発現制御に関わっている可能性を示唆する結果は、三次元ゲノム構造を標的とした新たなタイプの治療薬の開発につながると考えられる。