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

Author

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  • Tianyu Qu

    (First Affiliated Hospital of Nanjing Medical University)

  • Chang Zhang

    (Nanjing Medical University
    the Third Affiliated Hospital of Nanjing Medical University)

  • Xiyi Lu

    (First Affiliated Hospital of Nanjing Medical University)

  • Jiali Dai

    (First Affiliated Hospital of Nanjing Medical University)

  • Xuezhi He

    (Nanjing Medical University)

  • Wei Li

    (First Affiliated Hospital of Nanjing Medical University)

  • Liang Han

    (Xuzhou School of Clinical Medicine of Nanjing Medical University)

  • Dandan Yin

    (Gulou District)

  • Erbao Zhang

    (Nanjing Medical University
    Nanjing Medical University)

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.

Suggested Citation

  • Tianyu Qu & Chang Zhang & Xiyi Lu & Jiali Dai & Xuezhi He & Wei Li & Liang Han & Dandan Yin & Erbao Zhang, 2025. "8q24 derived ZNF252P promotes tumorigenesis by driving phase separation to activate c-Myc mediated feedback loop," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56879-7
    DOI: 10.1038/s41467-025-56879-7
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    1. Liu Teng & Yu Chen Feng & Su Tang Guo & Pei Lin Wang & Teng Fei Qi & Yi Meng Yue & Shi Xing Wang & Sheng Nan Zhang & Cai Xia Tang & Ting La & Yuan Yuan Zhang & Xiao Hong Zhao & Jin Nan Gao & Li Yuan W, 2021. "The pan-cancer lncRNA PLANE regulates an alternative splicing program to promote cancer pathogenesis," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. Mahmoud M. Elguindy & Joshua T. Mendell, 2021. "NORAD-induced Pumilio phase separation is required for genome stability," Nature, Nature, vol. 595(7866), pages 303-308, July.
    3. Marina Garcia-Jove Navarro & Shunnichi Kashida & Racha Chouaib & Sylvie Souquere & Gérard Pierron & Dominique Weil & Zoher Gueroui, 2019. "RNA is a critical element for the sizing and the composition of phase-separated RNA–protein condensates," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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