Biology subjects

de la Vega, L.

Publications and source records attributed to de la Vega, L..

5 recordsLinked to original sources

bioRxiv2025

Identification of a BACH1 lung cancer signature: A novel tool for understanding BACH1 biology and identifying new inhibitors.

The transcription factor BACH1 is a transcriptional repressor with a central role in regulating oxidative stress and anti-inflammatory pathways, emerging as a promising therapeutic target for multiple conditions, including neoplastic malignancies, neurodegenerative disorders, ischemia-reperfusion injuries and sickle cell disease. 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 address this, we performed RNA-Seq coupled with ChIP-Seq in BACH1-proficient and BACH1-deficient lung cancer cells, identifying 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 BACH1s pro-metastatic role.

cancer biology↗

bioRxiv2021

The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, are potent BACH1 inhibitors

The transcription factor BACH1 is a potential target against a variety of chronic conditions linked to oxidative stress and inflammation, and formation of cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2- cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these drugs may have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of CDDO-derivatives, but not CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-derivatives inhibit BACH1, which explains the much higher potency of CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-derivatives inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. Altogether, our study identifies CDDO-derivatives as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.

cell biology↗

bioRxiv2020

Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity

Oxidative stress and inflammation in the brain are two key hallmarks of neurodegenerative diseases (NDs) such as Alzheimers, Parkinsons, Huntingtons and multiple sclerosis. The axis NRF2-BACH1 has anti-inflammatory and anti-oxidant properties that could be exploited pharmacologically to obtain neuroprotective effects. Activation of NRF2 or inhibition of BACH1 are, individually, promising therapeutic approaches for NDs. Compounds with dual activity as NRF2 activators and BACH1 inhibitors, could therefore potentially provide a more robust antioxidant and anti-inflammatory effects, with an overall better neuroprotective outcome. The phytocannabinoid cannabidiol (CBD) inhibits BACH1 but lacks significant NRF2 activating properties. Based on this scaffold, we have developed a novel CBD derivative that is highly effective at both inhibiting BACH1 and activating NRF2. This new CBD derivative provides neuroprotection in cell models of relevance to Huntingtons disease, setting the basis for further developments in vivo.

cell biology↗

bioRxiv2019

The kinase inhibitor AT9283 selectively kills colorectal cancer cells with hyperactive NRF2

Aberrant hyperactivation of NRF2 is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis. The identification of ways to overcome the protection provided by NRF2 and selectively kill cancer cells addicted to NRF2 is a desirable goal. Exploiting the CRISPR/Cas9 technology, we generated colorectal cancer cell lines with hyperactive NRF2, and used them to perform a drug screen. We identified AT9283, an Aurora kinase inhibitor, for its selectivity towards killing cancer cells with hyperactive NRF2 as a consequence to either genetic or pharmacological activation. Our results show that hyperactivation of NRF2 presents a potential vulnerability that could be therapeutically exploited, and further suggest that AT9283, a drug that is currently in clinical trials, holds promise for the treatment of tumours with hyperactive NRF2.\n\nHighlightsO_LIWe present a new model for NRF2 hyperactivation in colorectal cancer cells.\nC_LIO_LIAT9283 selectively kills cancer cells with hyperactive NRF2\nC_LIO_LIBoth genetic and pharmacological activation of NRF2 sensitise cells to AT9283\nC_LI

cancer biology↗

bioRxiv2019

DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress and tumour growth in triple-negative breast cancer

To survive aneuploidy-induced proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive target. As developing HSF1 inhibitors is challenging, the identification and targeting of upstream regulators of HSF1 presents a tractable alternative strategy. Here we demonstrate that in triple negative breast cancer (TNBC) cells, the dual-specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. Thus, DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. In agreement with this, DYRK2 depletion reduces tumour growth in a TNBC xenograft model. These findings identify DYRK2 as both, a key modulator of the HSF1 transcriptional program, and a potential therapeutic target.

cancer biology↗