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The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity

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  • Laura Casares, University of Dundee
  • ,
  • Rita Moreno, University of Dundee
  • ,
  • Kevin X. Ali, University of Gothenburg
  • ,
  • Maureen Higgins, University of Dundee
  • ,
  • Sharadha Dayalan Naidu, University of Dundee
  • ,
  • Graham Neill, University of Dundee
  • ,
  • Lena Cassin
  • ,
  • Anders E. Kiib
  • Esben B. Svenningsen
  • Alberto Minassi, Università degli Studi del Piemonte Orientale
  • ,
  • Tadashi Honda, Stony Brook University
  • ,
  • Thomas B. Poulsen
  • Clotilde Wiel, University of Gothenburg
  • ,
  • Volkan I. Sayin, University of Gothenburg
  • ,
  • Albena T. Dinkova-Kostova, University of Dundee
  • ,
  • David Olagnier
  • Laureano de la Vega, University of Dundee

The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as 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 compounds 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 two CDDO-derivatives (CDDO-Me and CDDO-TFEA), but not of CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-Me and CDDO-TFEA inhibit BACH1, which explains the much higher potency of these CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-Me and CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both CDDO-derivatives impaired lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while CDDO was inactive. Altogether, our study identifies CDDO-Me and CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.

TidsskriftRedox Biology
Antal sider11
StatusUdgivet - maj 2022

Bibliografisk note

Funding Information:
This work was supported by the Medical Research Institute of the University of Dundee , Cancer Research UK ( C52419/A22869 and C20953/A18644 ) (LV and ADK), Tenovus Scotland ( T18/07 ) (LC) and Medical Research Scotland ( PhD-50058-2019 ). DO was supported by the Lundbeck Foundation ( R335-2019-2138 ), Kræftens Bekæmpelse ( R279-A16218 ), the Brødrene Hartman Fond , the Hørslev Fond, the fabrikant Einer Willumsens mindelegat, and the Eva og Henry Fraenkels Mindefond.

Publisher Copyright:
© 2022

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