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

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DOI

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

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.

OriginalsprogEngelsk
TidsskriftRedox Biology
Vol/bind51
Sider (fra-til)102291
ISSN2213-2317
DOI
StatusE-pub ahead of print - 17 mar. 2022

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Copyright © 2022. Published by Elsevier B.V.

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