Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism
Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism
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DOI：
10.1038/s41586-019-1005-x
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发表时间：
2019-04-11
期刊：
影响因子：
64.8
通讯作者：
Rosner, Marsha Rich
中科院分区：
文献类型：
--
作者：
Lee, Jiyoung;Yesilkanal, Ali E.;Rosner, Marsha Rich
线粒体代谢是癌症治疗的一个有吸引力的靶点（1，2）。重新编程代谢途径可以提高代谢抑制剂抑制治疗选择有限的癌症的能力，例如三阴性乳腺癌（TNBC）（1，3）。在这里，我们表明BTB和CNC同源性1（BACH 1）（4），一种在TNBC患者肿瘤中表达增加的血红素结合转录因子，靶向线粒体代谢。BACH1降低三羧酸循环中的葡萄糖利用率，并负调节电子传递链（ETC）基因的转录。通过shRNA消耗BACH1或通过氯化血红素降解使细胞对ETC抑制剂如二甲双胍敏感（5，6），抑制细胞系和患者来源的肿瘤异种移植物的生长。在表达BACH1短发夹RNA的细胞中表达血红素抗性BACH1突变体可挽救BACH1表型，并恢复经血红素处理的细胞和肿瘤中的二甲双胍抗性（7）。最后，BACH1基因表达与乳腺癌患者和其他肿瘤类型的肿瘤中ETC基因表达呈负相关，这突出了我们研究结果的临床相关性。这项研究表明，可以通过靶向BACH 1来利用线粒体代谢，使乳腺癌和潜在的其他肿瘤组织对线粒体抑制剂敏感。
Mitochondrial metabolism is an attractive target for cancer therapy(1,2). Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC)(1,3). Here we show that BTB and CNC homology1 (BACH1)(4), a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin(5,6), suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours(7). Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors.