Abstract
In solid tumors, hypoxia is a key driver of metastasis by promoting cellular plasticity and chromosomal instability (CIN). Despite this, the mechanisms by which malignant cells concurrently co-opt these elements of hypoxic adaptation to promote metastasis remains unclear. Here we report that hypoxia promotes metastasis by suppressing the JmjC-containing histone lysine demethylase KDM8. Kdm8 targeting in a Kras;Trp53-driven mouse model of pancreatic ductal adenocarcinoma induces a profound loss of the epithelial morphology and widespread metastatic disease. Mechanistically, Kdm8 suppression in normoxia recapitulates major aspects of the global epigenetic changes, transcriptomic rewiring, and mitotic spindle defects induced by hypoxia. Of note, disruption of Kdm8's demethylase function phenocopies the effects of Kdm8 loss, whereas expression of hypermorphic Kdm8 variants that are resistant to hypoxic suppression reduces metastasis beyond the levels achieved by the wildtype counterpart. Through the suppression of Kdm8 demethylase activity, hypoxia unleashes a potent metastatic program by simultaneously advancing cellular plasticity and CIN.