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p53-inducible lncRNA LOC644656 causes genotoxic stress-induced stem cell maldifferentiation and cancer chemoresistance

Author

Listed:
  • Ai Tamura

    (Chiba University)

  • Kazuyuki Yamagata

    (Chiba University)

  • Takashi Kono

    (Chiba University
    Chiba University)

  • Masanori Fujimoto

    (Chiba University)

  • Takahiro Fuchigami

    (Chiba University)

  • Motoi Nishimura

    (Chiba University Hospital)

  • Masataka Yokoyama

    (Chiba University)

  • Akitoshi Nakayama

    (Chiba University)

  • Naoko Hashimoto

    (Chiba University
    Chiba University)

  • Ikki Sakuma

    (Chiba University)

  • Nobuyuki Mitsukawa

    (Chiba University)

  • Yusuke Kawashima

    (Kisarazu)

  • Osamu Ohara

    (Kisarazu)

  • Shinichiro Motohashi

    (Chiba University)

  • Eiryo Kawakami

    (Chiba University)

  • Takashi Miki

    (Chiba University
    Graduate School of Medicine)

  • Atsushi Onodera

    (Chiba University
    Chiba University)

  • Tomoaki Tanaka

    (Chiba University
    Chiba University)

Abstract

Genotoxic stress-induced stem cell maldifferentiation (GSMD) integrates DNA damage responses with loss of stemness and lineage-specific differentiation to prevent damaged stem cell propagation. However, molecular mechanisms governing GSMD remain unclear. Here, we identify the p53-induced long non-coding RNA LOC644656 as a key regulator of GSMD in human embryonic stem cells. LOC644656 accumulates in the nucleus upon DNA damage, disrupting pluripotency by interacting directly with POU5F1 and KDM1A/LSD1-NuRD complexes, repressing stemness genes, and activating TGF-β signaling. Additionally, LOC644656 mitigates DNA damage by binding DNA-PKcs and modulating the DNA damage response. In cancer, elevated LOC644656 correlates with poor patient survival and enhanced chemoresistance. Our findings demonstrate that LOC644656 mediates stemness suppression and resistance to genotoxic stress by coordinating DNA damage signaling and differentiation pathways. Thus, LOC644656 represents a potential therapeutic target for overcoming chemoresistance and advancing stem cell biology.

Suggested Citation

  • Ai Tamura & Kazuyuki Yamagata & Takashi Kono & Masanori Fujimoto & Takahiro Fuchigami & Motoi Nishimura & Masataka Yokoyama & Akitoshi Nakayama & Naoko Hashimoto & Ikki Sakuma & Nobuyuki Mitsukawa & Y, 2025. "p53-inducible lncRNA LOC644656 causes genotoxic stress-induced stem cell maldifferentiation and cancer chemoresistance," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59886-w
    DOI: 10.1038/s41467-025-59886-w
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