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的乳腺癌亚型。不幸的是，多达 70% 的 TNBC 患者对治疗产生耐药性。导致化疗耐药的一个已知因素是功能失调的线粒体凋亡信号传导。我们建立了一个表型小分子筛选，以揭示 TNBC 细胞中不依赖于线粒体凋亡的脆弱性。使用功能遗传方法，我们发现“命中”化合物 BAS-2 与组蛋白脱乙酰酶抑制剂 (HDAC) 具有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地抑制 HDAC6。使用最先进的乙酰组质谱法，我们鉴定了 TNBC 细胞中 HDAC6 的糖酵解底物。我们证实抑制或敲除 HDAC6 可减少体外和体内的糖酵解代谢。通过一系列无偏见的筛选方法，我们已经确定了 HDAC6 在调节糖酵解代谢中的先前未知的作用。