Liquid-Liquid Phase Separation of ZKSCAN1 Drives Histone mRNA Polyadenylation in Cancer.

Cancer progression is driven by complex epigenetic dysregulation. Recently, elevated histone mRNA polyadenylation (pARDH) associated with ZKSCAN1 was proposed as a critical factor, however, its upstream mechanism is still elusive. Here, we explore how ZKSCAN1 regulates pARDH through liquid-liquid phase separation (LLPS), mediated by its intrinsically disordered region (IDR). Notably, knockdown of ZKSCAN1 in breast cancer cells markedly reduces pARDH levels. Mechanistically, immunoprecipitation coupled with mass spectrometry (IP-MS) identified 179 ZKSCAN1-interacting proteins (ZK-IPs), most of which were involved in mRNA processing and showed a positive correlation with pARDH levels. Moreover, ZKSCAN1-driven LLPS condensates enabled multivalent interactions with ZK-IPs, which regulated pARDH, disrupted chromatin structure, and subsequently affected cell cycle progression and immune pathways. These findings demonstrate that ZKSCAN1-mediated LLPS is a key regulator of epigenetic-immune crosstalk in cancer and highlights it as a potential therapeutic target.