Dual mechanism of DICER downregulation facilitates cancer metastasis

Figures & data

Figure 1. Two synergistic modes for DICER downregulation. HIF-1α (hypoxia-inducible factor-1α)-independent mechanism: Under hypoxia, the function of oxygen-sensitive demethylases KDM6A/B is inactivated and methyltransferase EZH2 activity increases for H3K27me3, suppressing transcription of DICER1.⁷ HIF-1α-dependent mechanism: Hypoxia-, IGF (Insulin-like growth factor)- and EGF (Epidermal growth factor)-induced HIF-1α mediate and enhance the binding of DICER and PARKIN. The interaction ubiquitinates DICER protein for autophagic–lysosomal degradation. These modes work synergistically to inhibit DICER expression, suppressing miRNA maturation. Subsequently, downregulation of miR-200b promotes ZEB1-mediated EMT of cells and cancer metastasis.⁵

Liu J, Zhang C, Zhao Y, Yue X, Wu H, Huang S, Chen J, Tomsky K, Xie H, Khella CA, et al. Parkin targets HIF-1alpha for ubiquitination and degradation to inhibit breast tumor progression. Nat Commun. 2017; (8):1823. PMID:29180628. doi:10.1038/s41467-017-01947-w.

 Google Scholar

Lai HH, Li JN, Wang MY, Huang HY, Croce CM, Sun HL, Lyu YJ, Kang JW, Chiu CF, Hung MC, et al. HIF-1α promotes autophagic proteolysis of Dicer and enhances tumor metastasis. J Clin Invest. 2018; (128):625–643. PMID:29251629. doi:10.1172/JCI89212.

 Google Scholar