TY - JOUR TI - Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer AU - Dowling, Catríona M. AU - Hollinshead, Kate E. R. AU - Grande, Alessandra Di AU - Pritchard, Justin AU - Zhang, Hua AU - Dillon, Eugene T. AU - Haley, Kathryn AU - Papadopoulos, Eleni AU - Mehta, Anita K. AU - Bleach, Rachel AU - Lindner, Andreas U. AU - Mooney, Brian AU - Düssmann, Heiko AU - O’Connor, Darran AU - Prehn, Jochen H. M. AU - Wynne, Kieran AU - Hemann, Michael AU - Bradner, James E. AU - Kimmelman, Alec C. AU - Guerriero, Jennifer L. AU - Cagney, Gerard AU - Wong, Kwok-Kin AU - Letai, Anthony G. AU - Chonghaile, Tríona Ní T2 - Science Advances AB - 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. Discovery of a new HDAC6 inhibitor reveals role for HDAC6 in the regulation of glycolytic metabolism. Discovery of a new HDAC6 inhibitor reveals role for HDAC6 in the regulation of glycolytic metabolism. DA - 2021/01/01/ PY - 2021 DO - 10.1126/sciadv.abc4897 DP - advances.sciencemag.org VL - 7 IS - 3 SP - eabc4897 LA - en SN - 2375-2548 UR - https://advances.sciencemag.org/content/7/3/eabc4897 Y2 - 2021/01/15/19:26:02 ER -