Abstract 199: Functional mechanism of hypoxia-inducible factor 1 alpha-mediated Dicer down-regulation

Abstract

MicroRNAs (miRNAs) are generated by a multiple steps process that post-transcriptionally regulate the expression of target genes. Dysregulation of miRNAs is linked to human diseases including the development of human cancer. Abrogation of cellular global miRNAs maturation has been proposed to promote tumorigenesis and cancer metastasis. Hypoxia stress is the major cause of dysregulation of miRNAs and promotes tumor angiogenesis, metastasis and tumorigenesis which is a pivotal factor to switch on the cellular oncogenic features during tumor progression. Although hypoxia stress regulates expression of a subset of miRNAs, the upstream regulators controlling miRNAs regulation under hypoxia remain unclear. This study demonstrates the molecular mechanism of post-translational regulation of Dicer under hypoxia. Our results show that knockdown of hypoxia inducible factor 1 alpha (HIF-1α) up-regulates Dicer expression in colorectal cancer (CRC) cells. Overexpression of HIF-1α enhances ubiquitination of Dicer and subsequently promotes it recognition by autophagic receptor for autophagy-lysosomal degradation. We also find that HIF-1α enhances cancer cell migration by regulating Dicer-regulated miRNAs. In conclusion, we demonstrated that HIF-1α down-regulated Dicer and abolishes miRNA biogenesis to enhance cancer cell migration. This study may provide a potential therapeutic direction that targets the dysregulated miRNAs in tumor hypoxia for patients with poor prognosis and metastatic CRC. Citation Format: Hui-Huang Lai, Yu-Jhen Lyu, Jie-Ning Li, Jen-Liang Su, Pai-Sheng Chen. Functional mechanism of hypoxia-inducible factor 1 alpha-mediated Dicer down-regulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 199. doi:10.1158/1538-7445.AM2015-199