HIF-1α, one of the most extensively studied oncogenes, is activated by a variety of microenvironmental factors. The resulting biological effects are thought to depend on its transcriptional activity. The RNAse enzyme Dicer is frequently downregulated in human cancers, which has been functionally linked to enhanced metastatic properties; however, current knowledge of the upstream mechanisms regulating Dicer is limited. In the present study, we identified Dicer as a HIF-1α–interacting protein in multiple types of cancer cell lines and different human tumors. HIF-1α downregulated Dicer expression by facilitating its ubiquitination by the E3 ligase Parkin, thereby enhancing autophagy-mediated degradation of Dicer, which further suppressed the maturation of known tumor suppressors, such as the microRNA let-7 and microRNA-200b. Consequently, expression of HIF-1α facilitated epithelial-mesenchymal transition (EMT) and metastasis in tumor-bearing mice. Thus, this study uncovered a connection between oncogenic HIF-1α and the tumor-suppressive Dicer. This function of HIF-1α is transcription independent and occurs through previously unrecognized protein interaction–mediated ubiquitination and autophagic proteolysis.

中文翻译：

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HIF- 1α促进Dicer的自噬蛋白水解并增强肿瘤转移

HIF-1α是研究最广泛的致癌基因之一，被多种微环境因子激活。据认为，产生的生物学效应取决于其转录活性。RNA酶Dicer在人类癌症中经常被下调，其功能与增强的转移特性有关。但是，目前对调节切块机的上游机制的了解是有限的。在本研究中，我们将Dicer鉴定为在多种类型的癌细胞系和不同人类肿瘤中的HIF-1α相互作用蛋白。HIF-1α通过促进E3连接酶Parkin的泛素化来下调Dicer的表达，从而增强Dicer的自噬介导的降解，从而进一步抑制了已知的肿瘤抑制因子（如microRNA let-7和microRNA-200b）的成熟。所以，HIF-1α的表达促进了荷瘤小鼠的上皮-间质转化（EMT）和转移。因此，本研究揭示了致癌性HIF-1α与抑癌切丁酶之间的联系。HIF-1α的这种功能与转录无关，并通过以前无法识别的蛋白质相互作用介导的泛素化和自噬蛋白水解发生。