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, Lindner Andreas U, Mooney Brian, Düssmann Heiko, O'Connor Darran, Prehn Jochen H M, Wynne Kieran, Hemann Michael, Bradner James E, Kimmelman Alec C, Guerriero Jennifer L, Cagney Gerard, Wong Kwok-Kin, Letai Anthony G, Chonghaile Tríona Ní
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Division of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
Sci Adv. 2021 Jan 15;7(3). doi: 10.1126/sciadv.abc4897. Print 2021 Jan.
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.
三阴性乳腺癌（TNBC）是一种没有靶向治疗形式的乳腺癌亚型。不幸的是，高达70%的TNBC患者会产生治疗抗性。已知化疗抗性的一个因素是线粒体凋亡信号功能失调。我们建立了一个表型小分子筛选，以揭示TNBC细胞中与线粒体凋亡无关的脆弱性。使用功能遗传学方法，我们确定一种“命中”化合物BAS-2具有与组蛋白去乙酰化酶抑制剂（HDAC）潜在相似的作用机制。体外HDAC抑制剂测定证实该化合物选择性抑制HDAC6。使用最先进的乙酰化蛋白质组质谱分析，我们确定了TNBC细胞中HDAC6的糖酵解底物。我们证实，抑制或敲除HDAC6在体外和体内均降低了糖酵解代谢。通过一系列无偏见的筛选方法，我们确定了HDAC6在调节糖酵解代谢中以前未被识别的作用。
