Hypoxia-induced phase separation of ZHX2 alters chromatin looping to drive cancer metastasis

Abstract

Hypoxia and dysregulated phase separation can both activate oncogenic transcriptomic profiles. However, whether hypoxia regulates transcription-associated phase separation remains unknown. Here, we find that zinc fingers and homeoboxes 2 (ZHX2) undergoes phase separation in response to hypoxia, promoting their occupancy on chromatin and activating a cluster of oncogene transcription that is enriched by metastatic genes distinct from the targets of hypoxia-inducible factor (HIF) and pathologically relevant to breast cancer. Hypoxia induces ZHX2 phase separation via a proline-rich intrinsically disordered region (IDR), enhancing phosphorylation of ZHX2 at S625 and S628 that incorporates CCCTC-binding factor (CTCF) in condensates to alter chromatin looping, consequently driving metastatic gene transcription and cancer metastasis. Our findings provide significant insight into oncogene activation and suggest a phase-separation-based therapeutic strategy for cancer.