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

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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16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)625-643
Number of pages19
JournalJournal of Clinical Investigation
Volume128
Issue number2
DOIs
Publication statusPublished - Feb 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Lai, H. H., Li, J. N., Wang, M. Y., Huang, H. Y., Croce, C. M., Sun, H. L., Lyu, Y. J., Kang, J. W., Chiu, C. F., Hung, M. C., Suzuki, H. I., & Chen, P. S. (2018). HIF-1α promotes autophagic proteolysis of dicer and enhances tumor metastasis. Journal of Clinical Investigation, 128(2), 625-643. https://doi.org/10.1172/JCI89212