近日，瑞士提契诺大学的Carlo V. Catapano研究团队的发现线粒体分裂的表观遗传调控参与促进人类前列腺癌肿瘤干细胞的自我更新。 2019年8月，国际知名学术期刊《细胞—代谢》发表了这一成果。

研究人员揭示了BRD4、线粒体动态和前列腺干细胞自我更新之间新的联系。通过靶向BRD4的基因敲减或化学抑制可阻断线粒体分裂、导致CSC耗竭以及致瘤性的丧失。在多种前列腺癌模型中均出现CSC的缺失，这表明前列腺癌的共同弱点以及对线粒体动态的依赖性。这些作用依赖于BRD4驱动的转录及其对线粒体分裂因（Mff）的抑制。Mff的表达下调重现了BRD4抑制的效果，而异位表达Mff则使前列腺CSC免于耗竭。这种通过BRD4抑制靶向CSC线粒体可塑性的新概念为开发更有效的前列腺癌治疗策略提供了一个新的范例。

据悉，癌症干细胞（CSC）可导致人类癌症的疾病进展和治疗失败。自我更新、分化和衰老之间的平衡决定了CSC是扩增还是逐渐减少。针对这些过程可能会产生新的抗癌疗法。

附：英文原文

Title: Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer

Author: Gianluca Civenni, Roberto Bosotti, Andrea Timpanaro, Esteban Cvitkovic, Giuseppina M. Carbone, Carlo V. Catapano, et al

Issue&Volume:  Volume 30 Issue 2

Abstract: Cancer stem cells (CSCs) contribute to disease progression and treatment failure in human cancers. The balance among self-renewal, differentiation, and senescence determines the expansion or progressive exhaustion of CSCs. Targeting these processes might lead to novel anticancer therapies. Here, we uncover a novel link between BRD4, mitochondrial dynamics, and self-renewal of prostate CSCs. Targeting BRD4 by genetic knockdown or chemical inhibitors blocked mitochondrial fission and caused CSC exhaustion and loss of tumorigenic capability. Depletion of CSCs occurred in multiple prostate cancer models, indicating a common vulnerability and dependency on mitochondrial dynamics. These effects depended on rewiring of the BRD4-driven transcription and repression of mitochondrial fission factor ( Mff). Knockdown of Mff reproduced the effects of BRD4 inhibition, whereas ectopic Mff expression rescued prostate CSCs from exhaustion. This novel concept of targeting mitochondrial plasticity in CSCs through BRD4 inhibition provides a new paradigm for developing more effective treatment strategies for prostate cancer.

DOI: https://doi.org/10.1016/j.cmet.2019.05.004

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30244-X