Identification of genomic elements that promote hormone-responsive transient expression of oncogenes

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07148
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kyoto University
• Principal Investigator: Shintaro Yamada 京都大学, 生命科学研究科, 特任講師 (20837869)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 性ホルモン / DNAトポイソメラーゼ / DNA二重鎖切断 / DNA修復 / 乳癌

Outline of Final Research Achievements

Receptors for sex hormones regulate transcription of various genes as transcription factors. During the transcriptional response after sex hormone stimulation, genomic breaks often occur at transcriptional regulatory sequences (promoters and enhancers) of target genes in a DNA topoisomerase II-dependent manner. If cells are unable to efficiently recombine these genomic breaks, the transcriptional response after sex hormone stimulation is greatly altered. In this study, we analyzed the early transcriptional response of prostate cancer cells exposed to the male hormone androgen. We found that mutants that accumulate refractory genomic truncations (TDP2) have enhanced early transcriptional responses, such as the c-MYC oncogene. Moreover, we identified enhancers whose activities correlate with those early transcriptional responses.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、ゲノム切断修復酵素が欠損した時の、外的刺激への転写応答変化を全ゲノムで解析した。その結果、TDP2と同様にゲノム切断の修復が異常になるATMやBRCA1、BRCA2の変異の保因者が前立腺癌を起こしやすい原因の一つが、アンドロゲン暴露時のエンハンサーの異常による発癌遺伝子の異常な転写応答である可能性が推察された。得られた成果は、ATM、BRCA1、BRCA2などのDNA損傷修復遺伝子の変異の保因者が、乳癌や卵巣癌、前立腺癌を発症しやすいか、その問いに答える分子メカニズムを解明するための基盤になる。