ZHX2 alters chromatin looping to drive cancer metastasis

But whether hypoxia regulates transcription-associated phase separation remains unknown. Here, we find that the transcription factor, zinc fingers and homeoboxes 2 (ZHX2), undergoes phase separation under hypoxia, thus promoting its occupancy on chromatin and activating transcription for a cluster of oncogenes, that is enriched by metastatic genes distinct from targets of hypoxia-inducible factor (HIF) and pathologically relevant to breast cancer.

Mechanistically, hypoxia induces phase separation of ZHX2 via a proline-rich intrinsically disordered region (IDR) in the nuclear localization sequence (NLS), thereby enhancing the 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 breast cancer metastasis. This fundamental mechanism provides significant insight into oncogene activation and suggests a phase separation-based therapeutic strategy for cancer.