Epigenetic Induction of Mitochondrial Fission Is Required for Maintenance of Liver Cancer-Initiating Cells
Epigenetic Induction of Mitochondrial Fission Is Required for Maintenance of Liver Cancer-Initiating Cells
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线粒体分裂的表观遗传诱导是维持肝癌起始细胞所必需的
DOI：
10.1158/0008-5472.can-21-0436
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发表时间：
2021-07-15
期刊：
影响因子：
11.2
通讯作者：
Song, Libing
中科院分区：
文献类型：
--
作者：
Tang, Miaoling;Yang, Meisongzhu;Song, Libing
线粒体动力学通过促进癌细胞的肿瘤引发潜力在各种类型的癌症的致瘤性和恶性度中起着至关重要的作用，这表明靶向驱动线粒体动力学的关键因素可能导致有希望的抗癌疗法。在目前的研究中，我们报告说，线粒体分裂因子（MFF）的过度表达，这是在肝癌启动细胞（LCIC）显著上调，促进线粒体分裂，增强非LCIC的干性和肿瘤启动能力。MFF诱导的线粒体分裂诱发线粒体自噬和不对称干细胞分裂，并促进从氧化磷酸化到糖酵解的代谢转变，从而减少线粒体活性氧（ROS）的产生，从而防止ROS介导的多能性转录因子OCT 4的降解。CRISPR原位亲和纯化调控元件显示，与非LCIC和肝祖细胞相比，在LCIC中独特过表达的T-box转录因子19（TBX 19）与LCIC中MFF启动子上的PRMT 1形成复合物，引发表观遗传组蛋白H4 R3 me 2a/H3 K9 ac介导的MFF反式激活。使用选择性药理学抑制剂呋喃脒靶向PRMT 1，抑制TBX 19诱导的线粒体分裂，导致LCIC自我更新潜力和肿瘤引发能力的严重丧失。这些发现揭示了线粒体分裂介导的癌症干性的一种新机制，并表明通过抑制PRMT 1来调节线粒体分裂可能是肝癌治疗的一种有吸引力的治疗选择。这些发现表明，TBX 19/PRMT 1复合物介导的MFF上调促进了肝癌细胞中的线粒体分裂和肿瘤起始能力，将PRMT 1鉴定为肝癌中可行的治疗靶点。
Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer-initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumorinitiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission-mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment.Significance: These findings show that TBX19/PRMT1 complexmediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.