科学家发现三阴性乳腺癌代谢新靶点
三阴性乳腺癌由于缺乏雌激素受体、孕激素受体、人类表皮生长因子受体HER2，故对现有主要的靶向治疗方法无效，全身治疗主要依靠化疗。不幸的是，高达70%的三阴性乳腺癌患者对化疗产生耐药。线粒体是细胞内氧化磷酸化和合成三磷酸腺苷的主要场所，可为细胞活动提供化学能量，故有细胞发电站之称。既往研究发现，线粒体凋亡信号传导功能障碍是化疗耐药的原因之一。
2021年1月15日，美国科学促进会《科学》旗下《科学进展》在线发表爱尔兰皇家外科医师学院、都柏林大学学院、美国纽约大学、宾夕法尼亚州立大学、哈佛大学医学院、达纳法伯癌症研究所、麻省理工学院的研究报告，通过表现型小分子筛选，发现了独立于线粒体凋亡的三阴性乳腺癌细胞化疗耐药靶点。
该研究利用功能基因法，确定靶向化合物BAS-2具有与组蛋白脱乙酰酶HDAC抑制剂相似的作用机制。体外HDAC抑制剂测定证实，该化合物可选择性抑制HDAC6。
利用最新的乙酰化修饰组质谱仪，该研究确定了三阴性乳腺癌细胞的HDAC6糖酵解底物，并且证实抑制或敲除HDAC6编码基因可减少体内和体外的糖酵解代谢。
因此，该研究通过一系列无偏倚筛选方法，确定了HDAC6对于调节三阴性乳腺癌糖酵解代谢的作用，并为BAS-2靶向治疗三阴性乳腺癌奠定了基础。
Sci Adv. 2021 Jan 15;7(3):eabc4897.
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. Guerriero, Gerard Cagney, Kwok-Kin Wong, Anthony G. Letai, Tríona Ní Chonghaile.
Royal College of Surgeons in Ireland, Dublin, Ireland; New York University Langone Medical Center, New York, NY, USA; The Pennsylvania State University, University Park, PA, USA; University College Dublin, Dublin, Ireland; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Massachusetts Institute of Technology, Cambridge, MA, USA.
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.
DOI: 10.1126/sciadv.abc4897