8q24 derived ZNF252P promotes tumorigenesis by driving phase separation to activate c-Myc mediated feedback loop.

Abstract

As a well-known cancer risk region, the 8q24 locus is frequently amplified in a variety of solid tumors. Here we identify a pseudogene-derived oncogenic lncRNA, ZNF252P, which is upregulated in a variety of cancer types by copy number gain as well as c-Myc-mediated transcriptional activation. Mechanistically, ZNF252P binds and drives "phase separation" of HNRNPK and ILF3 protein in the nucleus and cytoplasm, respectively, to transcriptionally and posttranscriptionally activate c-Myc, thus forming a c-Myc/ZNF252P/c-Myc positive feedback loop. These findings expand the understanding of the relationship between genomic instability in the 8q24 region and tumorigenesis and clarify a regulatory mechanism involved in transcription and posttranscription from the perspective of RNA-mediated nuclear and cytoplasmic protein phase separation, which sheds light on the dialogue with the driver oncogene c-Myc. The pivotal regulatory axis of ZNF252P/c-Myc has potential as a promising biomarker and therapeutic target in cancer development.