Effects of G-quadruplex in LaminA/C promoter on colon cancer phenotype

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17465
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Osaka International Cancer Institute
• Principal Investigator: Nishikawa Tatsuya 地方独立行政法人大阪府立病院機構大阪国際がんセンター(研究所), その他部局等, 腫瘍循環器科診療主任 (80781757)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: G-quadruplex / LMNA遺伝子 / Lamin A/C / 大腸がん

Outline of Final Research Achievements

Lamin A/C proteins, major components of the nuclear lamina, are encoded by the LMNA gene. Among the LMNA transcript variants, we focused on a spliced variant 6 (termed LMNA-V6), which contains unique 3 exons upstream of exon 1 of LMNA. The promoter region of LMNA-V6 formed multiple G-quadruplexes and increased its transcriptional activity. Moreover, LMNA-V6 negatively regulated other LMNA mRNA variants, lamin A and lamin C, via direct interaction with their promoter. Knockdown of LMNA-V6 decreased the proliferation of colon cancer cells, whereas overexpression of the unique 3 exons of LMNA-V6 increased cell growth. Furthermore, microarray gene expression profiling showed that alteration of LMNA-V6 levels influenced the expression of p53 in colon cancer cells. Taken together, the results suggest that LMNA-V6 may be a novel functional RNA whose expression is regulated through multiple G-quadruplexes in colon cancer cells.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

LMNA遺伝子はがん関連遺伝子の１つである。本研究では、LMNA遺伝子の転写産物のうち、LMNA-V6についてその存在を証明し、機能を解析した。LMNA-V6のプロモーター領域にはG-quadruplex構造をとる領域を認め、LMNA-V6の発現を制御していた。さらにLMNA-V6は新規の機能性RNAとして、Lamin A/CのmRNAの発現制御を行っていた。また、LMNA-V6は大腸がん細胞内で、p53遺伝子というがん抑制遺伝子の発現を変化させた。LMNV-V6の制御が今後のがんに対する治療法の発展に寄与できる可能性があり、有用な研究結果が得られた。