A lung cancer specific BACH1 transcriptional signature for identifying novel BACH1 inhibitors

The transcription factor BACH1 is a transcriptional repressor with a central role regulating oxidative stress and anti-inflammatory pathways, emerging as a promising therapeutic target for multiple conditions, including neurodegenerative disorders, ischemia-reperfusion injuries, sickle cell disease and cancer. In the field of cancer BACH1 has gained significant attention, with BACH1 overexpression correlating with poor prognosis and metastasis across various cancer types; however, despite this increasing relevance of BACH1, no universal pro-metastatic mechanism or transcriptional signature for BACH1 has been identified which is a major limitation for this growing field. To fill this gap, in this study we performed RNA-Seq coupled with ChIP-Seq in BACH1 proficient and deficient lung cancer cells and identified a set of common BACH1 directly regulated genes, which we thoroughly validated in a large panel of cancer cells. This novel lung cancer BACH1 transcriptional signature is highly sensitive and specific to BACH1 perturbations (both genetic and pharmacological) and does not respond to NRF2 modulation, underscoring its specificity. This signature not only represents a robust surrogate for BACH1 activity, but we also provide evidence of its potential value as a tool to i) identify novel BACH1 inhibitors; and ii) provide insights into BACH1’s pro-metastatic role. To identify BACH1-regulated genes in lung cancer cells and develop a transcriptional signature specific to BACH1

转录因子BACH1是一类转录阻遏物（transcriptional repressor），在调控氧化应激（oxidative stress）与抗炎通路（anti-inflammatory pathways）中发挥核心作用，现已成为多种疾病极具潜力的治疗靶点（therapeutic target），涵盖神经退行性疾病（neurodegenerative disorders）、缺血再灌注损伤（ischemia-reperfusion injuries）、镰状细胞病（sickle cell disease）及癌症（cancer）等。在癌症研究领域，BACH1已受到广泛关注：其过表达与多种癌症类型的不良预后（poor prognosis）及转移（metastasis）密切相关。然而，尽管BACH1的研究价值与日俱增，目前尚未发现通用的促转移机制或BACH1特异性转录特征（transcriptional signature），这已成为该研究领域的重大局限。为填补这一研究空白，本研究对BACH1功能正常与缺陷的肺癌细胞开展了RNA测序（RNA-Seq）与染色质免疫共沉淀测序（ChIP-Seq）联合分析，鉴定出一组共有的BACH1直接调控基因（directly regulated genes），并在大规模癌细胞系中完成了全面验证。这一全新的肺癌BACH1转录特征对BACH1扰动（包括遗传与药理学干预）具有高度敏感性与特异性，且不受核因子E2相关因子2（NRF2）调控的影响，进一步凸显了其特异性。该转录特征不仅可作为BACH1活性的可靠替代标志物，本研究还证实其具备双重应用价值：其一，可用于筛选新型BACH1抑制剂；其二，可为解析BACH1的促转移机制提供研究线索。本研究旨在鉴定肺癌细胞中受BACH1调控的基因，并开发特异性针对BACH1的转录特征。