Hypoxia Promotes Stem Cell Phenotypes, Resistance to Therapy and Poor Prognosis through Epigenetic Regulation of DICER

Hypoxia is a common characteristic of solid tumors, associated with aggressive disease and poor prognosis in multiple sites, including breast and cervix cancer. These properties are attributed to the influence of hypoxia on treatment resistance to both radiotherapy and chemotherapy as well as biological responses that promote altered tumor biology. Extensive research has led to a good understanding of the mechanisms of cellular adaptation to hypoxia, and regulation of metabolic and angiogenic phenotypes. However, considerably less is known regarding mechanisms responsible for the influence of hypoxia on metastasis and stemness. In a search to identify novel genes that contribute to the cellular response during hypoxia, we discovered that hypoxia represses DICER, a key enzyme required for generation of mature miRNA. DICER is a known haplo-insufficient tumor suppressor that can stimulate cancer development through a reduction in miRNA generation. We demonstrate that tumor hypoxia is a major regulator of DICER expression in large cohorts of breast cancer patients and that DICER expression is suppressed by hypoxia to levels similar to that in tumors with monoallelic DICER loss. We also demonstrate that DICER repression occurs through a novel epigenetic mechanism requiring inhibition of the oxygen-dependent H3K27me3 demethylases KDM6A/B. Hypoxic suppression of DICER creates a miRNA processing defect and results in selective reduction of mature levels of the miR-200 family. Consequently, hypoxia leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and results in acquisition of stem cell phenotypes in human mammary epithelial cells. Finally, we demonstrate the importance of reduced DICER in mediating therapeutic response to fractionated radiation treatment in vivo. Our work suggests that in breast cancer the acquisition of EMT and stem cell properties, through epigenetic repression of DICER and loss of miR-200, may drive the known association of hypoxia and poor clinical outcome.Ph.D.2018-11-02 00:00:0