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Dowling CM, Hollinshead KER, Di Grande A, et al. Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer. Sci Adv. 2021;7(3)doi: 10.1126/sciadv.abc4897.
Dowling, C. M., Hollinshead, K. E. R., Di Grande, A., Pritchard, J., Zhang, H., Dillon, E. T., Haley, K., Papadopoulos, E., Mehta, A. K., Bleach, R., Lindner, A. U., Mooney, B., Düssmann, H., O'Connor, D., Prehn, J. H. M., Wynne, K., Hemann, M., Bradner, J. E., Kimmelman, A. C., Guerriero, J. L., Cagney, G., Wong, K. K., Letai, A. G., & Chonghaile, T. N. (2021). Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer. Science advances, 7(3), . https://doi.org/10.1126/sciadv.abc4897
Dowling, Catríona M, et al. "Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer." Science advances vol. 7,3 (2021). doi: https://doi.org/10.1126/sciadv.abc4897
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 Jan 15;7(3). doi: 10.1126/sciadv.abc4897. Print 2021 Jan. PMID: 33523897; PMCID: PMC7810372.
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Sci Adv. 2021 Jan 15;7(3). doi: 10.1126/sciadv.abc4897. Print 2021 Jan.

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

Science advances

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 U Lindner, Brian Mooney, Heiko Düssmann, Darran O'Connor, Jochen H M Prehn, Kieran Wynne, Michael Hemann, James E Bradner, Alec C Kimmelman, Jennifer L Guerriero, Gerard Cagney, Kwok-Kin Wong, Anthony G Letai, Tríona Ní Chonghaile

Affiliations

  1. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
  2. Division of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
  3. Department of Radiation Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
  4. Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, USA.
  5. School of Biomolecular and Biomedical Science, Conway Institute of Biomedical and Biomolecular Sciences, University College Dublin, Dublin, Ireland.
  6. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  7. Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
  8. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
  9. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland. [email protected].

PMID: 33523897 PMCID: PMC7810372 DOI: 10.1126/sciadv.abc4897

Abstract

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.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

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