@article{6bc28b7032c248d086b37bd7488d334b,
title = "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.",
author = "Lai, {Hui Huang} and Li, {Jie Ning} and Wang, {Ming Yang} and Huang, {Hsin Yi} and Croce, {Carlo M.} and Sun, {Hui Lung} and Lyu, {Yu Jhen} and Kang, {Jui Wen} and Chiu, {Ching Feng} and Hung, {Mien Chie} and Suzuki, {Hiroshi I.} and Chen, {Pai Sheng}",
note = "Funding Information: We thank Liang-Yi Hung, Chih-Peng Chang, and Hsiao-Sheng Liu for their technical support. We thank Kohei Miyazono for providing FLAG-tagged Dicer-expressing plasmid. We thank Kalle Gehring, V. Narry Kim, Gregory J. Goodall, Christopher B. Burge, Ashish Lal, and Judy Lieberman for sharing their plasmids with Addgene. We are grateful to Sheng-Hsiang Lin for providing statistical consulting services from the Biostatistics Consulting Center, NCKU Hospital. We are grateful for the support from the Human Biobank, Research Center of Clinical Medicine, and the Cancer Data Bank of NCKU Hospital. We thank the National RNAi Core Facility at Academia Sinica in Taiwan for providing shRNA reagents and related services. Mass spectrometry analy-ses were performed by Research Facility for Sharing at NHRI, Taiwan (Core Facilities for Proteomics and Chemistry). We thank the staff of the Biomedical Resource Core at the First Core Labs, National Taiwan University College of Medicine, for technical assistance. This study was supported by the Ministry of Science and Technology, Taiwan (MOST 103-2628-B-006-003- MY3, MOST 105-2320-B-006-050, MOST 106-2320-B-006-038, MOST 106-2320-B-006-021). Funding Information: We thank Liang-Yi Hung, Chih-Peng Chang, and Hsiao-Sheng Liu for their technical support. We thank Kohei Miyazono for providing FLAG-tagged Dicer-expressing plasmid. We thank Kalle Gehring, V. Narry Kim, Gregory J. Goodall, Christopher B. Burge, Ashish Lal, and Judy Lieberman for sharing their plasmids with Addgene. We are grateful to Sheng-Hsiang Lin for providing statistical consulting services from the Biostatistics Consulting Center, NCKU Hospital. We are grateful for the support from the Human Biobank, Research Center of Clinical Medicine, and the Cancer Data Bank of NCKU Hospital. We thank the National RNAi Core Facility at Academia Sinica in Taiwan for providing shRNA reagents and related services. Mass spectrometry analy- ses were performed by Research Facility for Sharing at NHRI, Taiwan (Core Facilities for Proteomics and Chemistry). We thank the staff of the Biomedical Resource Core at the First Core Labs, National Taiwan University College of Medicine, for technical assistance. This study was supported by the Ministry of Science and Technology, Taiwan (MOST 103-2628-B-006-003-MY3, MOST 105-2320-B-006-050, MOST 106-2320-B-006-038, MOST 106-2320-B-006-021).",
year = "2018",
month = feb,
day = "1",
doi = "10.1172/JCI89212",
language = "English",
volume = "128",
pages = "625--643",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",
}
