Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway
Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway
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DOI：
10.1038/s41419-019-2155-3
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发表时间：
2019-12-09
影响因子：
9
通讯作者：
Wong, Carmen Chak-Lui
中科院分区：
文献类型：
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作者：
Chiu, David Kung-Chun;Tse, Aki Pui-Wah;Wong, Carmen Chak-Lui
缺氧在癌症中很常见。缺氧，由于缺乏氧（O-2）作为电子受体，导致电子传递效率低下，通过电子传递链在线粒体导致活性氧（ROS）的积累，这可能会造成不可逆的细胞损伤。细胞通过缺氧诱导因子1（HIF-1）引发各种分子事件，从而克服低O-2。了解HIF-1调控的新分子机制对于靶向低氧肿瘤的新治疗干预非常重要。以肝细胞癌（HCC）为模型，我们揭示了HIF-1和Notch信号通路相互作用以控制癌细胞的线粒体生物合成，从而维持REDOX平衡。从转录组测序，我们发现，HEY 1，转录阻遏物，在NOTCH途径，一致诱导缺氧在肝癌细胞系。我们通过染色质免疫沉淀（ChIP）和荧光素酶报告基因检测在HEY 1中鉴定了一个强缺氧反应元件（HRE）。转录组和ChIP测序进一步确定PINK 1，线粒体生物合成所必需的基因，作为HEY 1的一个新的转录靶点。HEY 1敲低的HCC细胞重新表达PINK 1。HEY 1和PINK 1表达在人HCC样品中呈负相关。HEY 1的过表达和PINK 1的低表达在人HCC中被检测到，并且与不良的临床结果相关。在功能上，我们发现HEY 1的过表达或PINK 1的敲低一致地减少线粒体嵴、线粒体质量、氧化应激水平，并增加HCC生长。
Hypoxia is commonly found in cancers. Hypoxia, due to the lack of oxygen (O-2) as the electron recipient, causes inefficient electron transfer through the electron transport chain at the mitochondria leading to accumulation of reactive oxygen species (ROS) which could create irreversible cellular damages. Through hypoxia-inducible factor 1 (HIF-1) which elicits various molecular events, cells are able to overcome low O-2. Knowledge about the new molecular mechanisms governed by HIF-1 is important for new therapeutic interventions targeting hypoxic tumors. Using hepatocellular carcinoma (HCC) as a model, we revealed that the HIF-1 and the Notch signaling pathways cross-talk to control mitochondrial biogenesis of cancer cells to maintain REDOX balance. From transcriptome sequencing, we found that HEY1, a transcriptional repressor, in the NOTCH pathway was consistently induced by hypoxia in HCC cell lines. We identified a strong hypoxia response element (HRE) in HEY1 by chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Transcriptome and ChIP sequencing further identified PINK1, a gene essential for mitochondrial biogenesis, as a novel transcriptional target of HEY1. HCC cells with HEY1 knockdown re-expressed PINK1. HEY1 and PINK1 expressions inversely correlated in human HCC samples. Overexpression of HEY1 and underexpression of PINK1 were detected in human HCC and associated with poor clinical outcomes. Functionally, we found that overexpression of HEY1 or knockdown of PINK1 consistently reduced mitochondrial cristae, mitochondrial mass, oxidative stress level, and increased HCC growth.