Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer
Name
eabc4897.full.pdf
Description
Published version
Size
1.44 MB
Format
Unknown
Checksum (MD5)
01e95589396e5e56ee60da19cae1b7ca
Author(s)
Dowling, Catríona M.
Hollinshead, Kate E. R.
Di Grande, Alessandra
Pritchard, Justin
Zhang, Hua
Dillon, Eugene T.
Haley, Kathryn
Papadopoulos, Eleni
Mehta, Anita K.
Bleach, Rachel
Date Issued
January 2021
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Version
Final published version
Abstract
© 2021 American Association for the Advancement of Science. All rights reserved. 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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution NonCommercial License 4.0
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1126/sciadv.abc4897
