HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation.
HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation.
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HIF-1α 诱导的 m6A 阅读器 YTHDF1 表达通过促进 ATG2A 和 ATG14 翻译驱动缺氧诱导的自噬和肝细胞癌的恶性
DOI：
10.1038/s41392-020-00453-8
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发表时间：
2021-02-23
影响因子：
39.3
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Li Q;Ni Y;Zhang L;Jiang R;Xu J;Yang H;Hu Y;Qiu J;Pu L;Tang J;Wang X
n6 -甲基腺苷（m6A）及其解读蛋白YTHDF1通过影响RNA代谢的几乎每个阶段在人类肿瘤发生中发挥关键作用。自噬激活是癌细胞在缺氧条件下存活的途径之一。然而，在人肝细胞癌（HCC）中，m6A修饰mRNA是否可能参与缺氧诱导的自噬尚不清楚。在这项研究中，在YTHDF1过表达、敲除和敲低的HCC细胞、HCC类器官和HCC患者来源的异种移植（PDX）小鼠模型中检测到YTHDF1表达的特异性变化。体外实验中，YTHDF1的表达与缺氧诱导的自噬有显著相关性；YTHDF1在HCC组织中显著过表达与预后不良相关。多因素cox回归分析发现，YTHDF1表达是HCC患者的独立预后因素。多种肝癌模型证实，缺乏YTHDF1可抑制肝癌自噬、生长和转移。荧光素酶报告基因检测和染色质免疫沉淀表明，HIF-1α在缺氧条件下通过直接结合YTHDF1启动子区来调节YTHDF1的转录。甲基化RNA免疫沉淀测序、蛋白质组学和多体分析结果表明，YTHDF1通过与m6a修饰的ATG2A和ATG14 mRNA结合，促进了自噬相关基因ATG2A和ATG14的翻译，从而促进了HCC的自噬和自噬相关的恶性肿瘤。综上所述，hif -1α-诱导的YTHDF1表达通过以m6a依赖的方式促进自噬相关基因ATG2A和ATG14的翻译，与缺氧诱导的自噬和自噬相关的HCC进展相关。我们的研究结果表明，YTHDF1是HCC患者潜在的预后生物标志物和治疗靶点。
N6-methyladenosine (m6A), and its reader protein YTHDF1, play a pivotal role in human tumorigenesis by affecting nearly every stage of RNA metabolism. Autophagy activation is one of the ways by which cancer cells survive hypoxia. However, the possible involvement of m6A modification of mRNA in hypoxia-induced autophagy was unexplored in human hepatocellular carcinoma (HCC). In this study, specific variations in YTHDF1 expression were detected in YTHDF1-overexpressing, -knockout, and -knockdown HCC cells, HCC organoids, and HCC patient-derived xenograft (PDX) murine models. YTHDF1 expression and hypoxia-induced autophagy were significantly correlated in vitro; significant overexpression of YTHDF1 in HCC tissues was associated with poor prognosis. Multivariate cox regression analysis identified YTHDF1 expression as an independent prognostic factor in patients with HCC. Multiple HCC models confirmed that YTHDF1 deficiency inhibited HCC autophagy, growth, and metastasis. Luciferase reporter assays and chromatin immunoprecipitation demonstrated that HIF-1α regulated YTHDF1 transcription by directly binding to its promoter region under hypoxia. The results of methylated RNA immunoprecipitation sequencing, proteomics, and polysome profiling indicated that YTHDF1 contributed to the translation of autophagy-related genes ATG2A and ATG14 by binding to m6A-modified ATG2A and ATG14 mRNA, thus facilitating autophagy and autophagy-related malignancy of HCC. Taken together, HIF-1α-induced YTHDF1 expression was associated with hypoxia-induced autophagy and autophagy-related HCC progression via promoting translation of autophagy-related genes ATG2A and ATG14 in a m6A-dependent manner. Our findings suggest that YTHDF1 is a potential prognostic biomarker and therapeutic target for patients with HCC.
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