線粒體代謝是很有吸引力的癌癥治療靶點，在不改變基因序列的情況下，對代謝通路進行重編程，可以提高線粒體代謝抑制劑（例如二甲雙胍）對癌癥的抑制能力，尤其對于治療選擇有限的三陰性乳腺癌。
2019年3月6日，全球自然科學三大旗艦期刊之一、英國《自然》正刊在線發(fā)表美國芝加哥大學、杜克大學、伯克利加利福尼亞大學、芝加哥伊利諾伊大學、威斯康星醫(yī)學院的研究報告，發(fā)現(xiàn)了一種有效針對乳腺癌線粒體代謝的聯(lián)合療法。
該研究表明，針對線粒體代謝的血紅素轉(zhuǎn)錄調(diào)節(jié)蛋白——BTB和CNC同源蛋白1（BACH1）高表達于三陰性乳腺癌患者的腫瘤。BACH1可以減少三羧酸循環(huán)的葡萄糖利用率，并且抑制線粒體內(nèi)膜電子傳遞鏈基因的轉(zhuǎn)錄。通過短發(fā)夾RNA抑制BACH1編碼基因表達或者通過氯化血紅素降解BACH1，可以使細胞對線粒體內(nèi)膜電子傳遞鏈抑制劑（例如二甲雙胍）敏感，從而抑制細胞株和患者來源腫瘤異種移植物的生長。如果表達BACH1短發(fā)夾RNA的細胞發(fā)生抗血紅素BACH1突變，可以恢復BACH1的表現(xiàn)型，并且恢復氯化血紅素處理細胞和腫瘤的二甲雙胍耐藥性。最后，該研究表明，BACH1基因表達與乳腺癌和其他腫瘤患者的腫瘤電子傳遞鏈基因表達成反比，證實了該研究的臨床意義。
因此，該研究結(jié)果表明，可以通過聯(lián)合BACH1靶向抑制劑或降解劑，使三陰性乳腺癌和其他腫瘤對線粒體代謝抑制劑（例如二甲雙胍）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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