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

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. GuerrieroGerard Cagney, Kwok Kin Wong, Anthony G. Letai, Tríona Ní Chonghaile

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbereabc4897
JournalScience Advances
Volume7
Issue number3
DOIs
StatePublished - Jan 15 2021

All Science Journal Classification (ASJC) codes

  • General

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