Identification of a BACH1 lung cancer signature: A novel tool for understanding BACH1 biology and identifying new inhibitors
Donika Klenja-Skudrinja, Kevin X. Ali, David Walker, Maureen Higgins, Angana AH. Patel, Dorota Raj, Anna Creelman, Charlotte McDowall, Conor Taylor, Tomasz Wenta, Erik Larsson, Clotilde Wiel, Volkan I. Sayin, Laureano de la Vega
Abstract
BACH1 is a transcriptional repressor that regulates oxidative stress and inflammatory responses and has emerged as a promising therapeutic target in cancer and other diseases. In lung cancer, BACH1 overexpression is linked to poor prognosis and metastasis, yet a consistent transcriptional signature reflecting its activity has not yet been defined. To address this, we performed RNA-Seq coupled with ChIP-Seq in BACH1-proficient and BACH1-deficient lung cancer cells, identifying a set of direct BACH1 target genes. This novel lung cancer BACH1 signature is highly sensitive and specific to BACH1 perturbation, unaffected by NRF2 modulation, and consistent across a large panel of cancer cell lines. Despite NRF2 binding to the same regions, BACH1-mediated gene repression is dominant over NRF2-driven gene activation, suggesting a previously unappreciated regulatory hierarchy between these two transcription factors. Importantly, this signature correlates with BACH1 basal levels in lung cancer, PDAC and melanoma cells, highlighting its relevance as a surrogate for BACH1 activity. Using this signature, we identified paeoniflorin as a novel FBXO22-dependent BACH1 degrader with anti-invasive activity, and the novel BACH1 target gene HTRA3 as a potential effector of BACH1's pro-migratory effect. In summary, this novel BACH1 signature holds potential as a therapeutically relevant biomarker for identifying lung tumours with elevated BACH1 activity, serves as a powerful platform for discovering anti-invasive BACH1 inhibitors, and provides mechanistic insights into BACH1's role in driving metastasis.