Molecular mechanisms of development of malignant female cancers associated with X-chromosome reactivation

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K19404
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Kitagawa Masatoshi 浜松医科大学, 医学部, 教授 (50294971)
• Co-Investigator(Kenkyū-buntansha): 丹伊田 浩行 浜松医科大学, 医学部, 准教授 (20336671) ; 大畑 樹也 浜松医科大学, 医学部, 助教 (80616459) ; 酒井 聡 浜松医科大学, 医学部, 助教 (50566081)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Keywords: X染色体 / 相同組換え修復 / 乳がん

Outline of Final Research Achievements

In female somatic cells, one side of the X chromosome is inactivated (XaXi), but in ES cells and iPS cells it is XaXa. XaXa is also seen with some frequency in human breast cancer cells. We found that female ES cells have lower homologous recombination (HR) ability than males. However, the molecular mechanism of HR suppression by activation of both X chromosomes is unknown. In this study, we searched for the responsible gene by RNA-Seq analysis and found a candidate gene, BRCC3. It was found that knocking down BRCC3 with female ES (XaXa) restored HR, suggesting that BRCC3 is the gene whose expression is upregulated by activation of both X chromosomes and acts to suppress homologous recombination.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

我々は、両X染色体が活性化状態にあるメスのES細胞(XaXa)はオス(XY)に比べて相同組換え(HR) 修復能が低いことを見出した。我々はin silico解析よりXsit低発現のヒト乳がん(XaXaの可能性が高い)では予後不良であることに気がつき、 「女性腫瘍で両X染色体の活性化が起こるとHR修復が抑制され、DNA障害が修復され難くなり、悪性度の亢進を来す可能性がある」と仮説を立てた。本研究により両X染色体活性化に伴う相同組換えの低下の原因がBRCA1複合体抑制遺伝子のBRCC3の過剰発現であることが判明した。本研究により女性腫瘍進展の分子機構の理解と克服に貢献が期待できる。