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线粒体代谢是很有吸引力的癌症治疗靶点，在不改变基因序列的情况下，对代谢通路进行重编程，可以提高线粒体代谢抑制剂（例如二甲双胍）对癌症的抑制能力，尤其对于治疗选择有限的三阴性乳腺癌。 2019年3月6日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表美国芝加哥大学、杜克大学、伯克利加利福尼亚大学、芝加哥伊利诺伊大学、威斯康星医学院的研究报告，发现了一种有效针对乳腺癌线粒体代谢的联合疗法。 该研究表明，针对线粒体代谢的血红素转录调节蛋白——BTB和CNC同源蛋白1（BACH1）高表达于三阴性乳腺癌患者的肿瘤。BACH1可以减少三羧酸循环的葡萄糖利用率，并且抑制线粒体内膜电子传递链基因的转录。通过短发夹RNA抑制BACH1编码基因表达或者通过氯化血红素降解BACH1，可以使细胞对线粒体内膜电子传递链抑制剂（例如二甲双胍）敏感，从而抑制细胞株和患者来源肿瘤异种移植物的生长。如果表达BACH1短发夹RNA的细胞发生抗血红素BACH1突变，可以恢复BACH1的表现型，并且恢复氯化血红素处理细胞和肿瘤的二甲双胍耐药性。最后，该研究表明，BACH1基因表达与乳腺癌和其他肿瘤患者的肿瘤电子传递链基因表达成反比，证实了该研究的临床意义。 因此，该研究结果表明，可以通过联合BACH1靶向抑制剂或降解剂，使三阴性乳腺癌和其他肿瘤对线粒体代谢抑制剂（例如二甲双胍）敏感。 Nature. 2019 Mar 6. [Epub ahead of print] Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism. Jiyoung Lee, Ali E. Yesilkanal, Joseph P. Wynne, Casey Frankenberger, Juan Liu, Jielin Yan, Mohamad Elbaz, Daniel C. Rabe, Felicia D. Rustandy, Payal Tiwari, Elizabeth A. Grossman, Peter C. Hart, Christie Kang, Sydney M. Sanderson, Jorge Andrade, Daniel K. Nomura, Marcelo G. Bonini, Jason W. Locasale, Marsha Rich Rosner. University of Chicago, Chicago, IL, USA; Duke University, Durham, NC, USA; University of California at Berkeley, Berkeley, CA, USA; University of Illinois at Chicago, Chicago, IL, USA; Medical College of Wisconsin, Milwaukee, WI, USA. Mitochondrial metabolism is an attractive target for cancer therapy. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC). Here we show that BTB and CNC homology1 (BACH1), 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, 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. 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. DOI: 10.1038/s41586-019-1005-x |
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