HIF-1α promotes autophagic proteolysis of Dicer and enhances tumor metastasis
Hui-Huang Lai, … , Hiroshi I. Suzuki, Pai-Sheng Chen
Hui-Huang Lai, … , Hiroshi I. Suzuki, Pai-Sheng Chen
Published December 18, 2017
Citation Information: J Clin Invest. 2018;128(2):625-643. https://doi.org/10.1172/JCI89212.
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Research Article Cell biology

HIF-1α promotes autophagic proteolysis of Dicer and enhances tumor metastasis

Abstract

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.

Authors

Hui-Huang Lai, Jie-Ning Li, Ming-Yang Wang, Hsin-Yi Huang, Carlo M. Croce, Hui-Lung Sun, Yu-Jhen Lyu, Jui-Wen Kang, Ching-Feng Chiu, Mien-Chie Hung, Hiroshi I. Suzuki, Pai-Sheng Chen

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Figure 5

HIF-1α recruits Parkin to interact with Dicer for autophagic proteolysis.

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HIF-1α recruits Parkin to interact with Dicer for autophagic proteolysis...
(A–C) Roles of HIF-1α in the recruitment of Parkin to Dicer. Associations between Dicer and Parkin in HCT116/shHIF-1α (A), HCT116/HIF-1α (B), and IGF-treated HCT116 (C) cells were detected. The immunoblots presented were derived from replicate samples run on parallel gels (B). (D and E) Effects of Parkin knockdown on the interaction between p62 and Dicer. Immunoprecipitates isolated by anti-Dicer antibodies were harvested to detect the protein association with p62 (D). The immunoblots presented were derived from replicate samples run on parallel gels. (E) Immunofluorescence analysis was performed using anti-p62, anti-Dicer antibodies, and DAPI for nuclear staining. Images were obtained by using confocal microscopy, as indicated: Dicer (red); p62 (green); DAPI (blue) (E, left). The spots of p62 and Dicer were quantified by using ImageJ (E, right). The experiments in B–E were performed in the presence of CQ and NH4Cl to block autophagy-lysosomal degradation. Original magnification: × 1000. Data are presented as mean ± SD, with at least n = 3 per group. Multigroup comparisons were analyzed by 1-way ANOVA with Tukey’s post hoc test. ***P < 0.001.