Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, Washington, DC 20037, USA.
Animal Research, Office of the Vice Provost for Research, 1922 F Street NW, Washington, DC 20052, USA.
Cells. 2022 Mar 31;11(7):1177. doi: 10.3390/cells11071177.
The oncogenic expression or mutation of tumor suppressors drives metabolic alteration, causing cancer cells to utilize diverse nutrients. Lactate is a known substrate for cancer cells, yet the regulatory mechanisms of lactate catabolism are limited. Here, we show that a heme-binding transcription factor, BACH1, negatively regulates lactate catabolic pathways in triple-negative breast cancer (TNBC) cells. BACH1 suppresses the transcriptional expression of monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase B, inhibiting lactate-mediated mitochondrial metabolism. In our studies, the depletion of BACH1 either genetically or pharmacologically increased the lactate use of TNBC cells, increasing their sensitivity to MCT1 inhibition. Thus, small inhibitory molecules (SR13800 and AZD3965) blocking MCT1 better suppressed the growth of BACH1-depleted TNBC cells than did the controls. Particularly, hemin treatment degrading BACH1 proteins induced lactate catabolism in TNBC cells, generating synthetic lethality with MCT1 inhibition. Our data indicates that targeting BACH1 generates metabolic vulnerability and increases sensitivity to lactate transporter inhibition, suggesting a potential novel combination therapy for cancer patients with TNBC.
致癌表达或肿瘤抑制因子的突变导致代谢改变，使癌细胞利用多种营养物质。乳酸是癌细胞的已知底物，但乳酸代谢的调节机制有限。在这里，我们表明，一种血红素结合转录因子 BACH1，负调控三阴性乳腺癌 (TNBC) 细胞中的乳酸分解代谢途径。BACH1 抑制单羧酸转运蛋白 1 (MCT1) 和乳酸脱氢酶 B 的转录表达，抑制乳酸介导的线粒体代谢。在我们的研究中，BACH1 的基因缺失或药理学缺失增加了 TNBC 细胞对乳酸的利用，增加了它们对 MCT1 抑制的敏感性。因此，小抑制分子 (SR13800 和 AZD3965) 阻断 MCT1 对 BACH1 缺失的 TNBC 细胞的抑制作用优于对照组。特别是，血红素处理降解 BACH1 蛋白诱导 TNBC 细胞中的乳酸分解代谢，与 MCT1 抑制产生合成致死性。我们的数据表明，靶向 BACH1 可产生代谢脆弱性，并增加对乳酸转运蛋白抑制的敏感性，为三阴性乳腺癌患者提供了一种潜在的新的联合治疗方法。
