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Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer

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posted on 10.06.2021, 15:04 authored by Catríona M Dowling, Kate E R Hollinshead, Alessandra Di Grande, Justin Pritchard, Hua Zhang, Eugene T Dillon, Kathryn Haley, Eleni Papadopoulos, Anita K Mehta, Rachel Bleach, Andreas Ulrich LindnerAndreas Ulrich Lindner, Brian Mooney, Heiko DuessmannHeiko Duessmann, Darran O'ConnorDarran O'Connor, Jochen PrehnJochen Prehn, Kieran Wynne, Michael Hemann, James E Bradner, Alec C Kimmelman, Jennifer L Guerriero, Gerard Cagney, Kwok-Kin Wong, Anthony G Letai, Triona Ni ChonghaileTriona Ni Chonghaile
Triple-negative breast cancer (TNBC) is a subtype of breast cancer without a targeted form of therapy. Unfortunately, up to 70% of patients with TNBC develop resistance to treatment. A known contributor to chemoresistance is dysfunctional mitochondrial apoptosis signaling. We set up a phenotypic small-molecule screen to reveal vulnerabilities in TNBC cells that were independent of mitochondrial apoptosis. Using a functional genetic approach, we identified that a "hit" compound, BAS-2, had a potentially similar mechanism of action to histone deacetylase inhibitors (HDAC). An in vitro HDAC inhibitor assay confirmed that the compound selectively inhibited HDAC6. Using state-of-the-art acetylome mass spectrometry, we identified glycolytic substrates of HDAC6 in TNBC cells. We confirmed that inhibition or knockout of HDAC6 reduced glycolytic metabolism both in vitro and in vivo. Through a series of unbiased screening approaches, we have identified a previously unidentified role for HDAC6 in regulating glycolytic metabolism.

Funding

Determining the mechanism of action of a novel histone deacetylase 6 specific inhibitor that kills chemoresistant breast cancer. | Funder: Wellcome Trust | Grant ID: 202079/Z/16/Z

The development of a novel HDAC6 inhibitor that can kill chemoresistant breast cancers | Funder: UNESCO (United Nations Educational, Scientific and Cultural Organization) | Grant ID: N/A

Breast Cancer Now 2016NovPR849

L’Oréal-UNESCO UK & I FWIS Fellowship

Science Foundation Ireland 19/FFP/6461

Irish Research Council Postdoctoral Fellowship GOIPD/2017/1271

H2020 MSCA Global Fellowship (799724)

NIH R35CA242427

History

Comments

The original article is available at https://advances.sciencemag.org

Published Citation

Dowling CM, Hollinshead KER, Di Grande A, Pritchard J, Zhang H, Dillon ET, Haley K, Papadopoulos E, Mehta AK, Bleach R, Lindner AU, Mooney B, Düssmann H, O'Connor D, Prehn JHM, Wynne K, Hemann M, Bradner JE, Kimmelman AC, Guerriero JL, Cagney G, Wong KK, Letai AG, Chonghaile TN. Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer. Sci Adv. 2021;7(3):eabc4897.

Publication Date

15 January 2021

PubMed ID

33523897

Department/Unit

  • Physiology and Medical Physics
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Cancer
  • Neurological and Psychiatric Disorders

Publisher

American Association for the Advancement of Science (AAAS)

Version

  • Published Version (Version of Record)