p53-inducible lncRNA LOC644656 causes genotoxic stress-induced stem cell maldifferentiation and cancer chemoresistance
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.
Authors
- Nobuyuki Mitsukawa (ORCID: https://orcid.org/0000-0002-0234-8241)
- Kazuyuki Yamagata (ORCID: https://orcid.org/0000-0002-5804-6090)
- Takashi Miki (ORCID: https://orcid.org/0000-0001-5741-1626)
- Tomoaki Tanaka (ORCID: https://orcid.org/0000-0002-9761-1750)
- Eiryo Kawakami (ORCID: https://orcid.org/0000-0001-9955-4342)
- Yusuke Kawashima (ORCID: https://orcid.org/0000-0002-9779-8199)
- Shinichiro Motohashi (ORCID: https://orcid.org/0000-0002-9332-3129)
- Takahiro Fuchigami (ORCID: https://orcid.org/0000-0002-6946-1345)
- Atsushi Onodera (ORCID: https://orcid.org/0000-0002-3715-9408)
- Osamu Ohara (ORCID: https://orcid.org/0000-0002-3328-9571)
- Naoko Hashimoto (ORCID: https://orcid.org/0000-0002-3229-3421)
- Ai Tamura
- Nishimura Motoi
- Akitoshi Nakayama
- Masanori Fujimoto (ORCID: https://orcid.org/0000-0003-1458-8207)
- Ikki Sakuma
- Takashi Kono (ORCID: https://orcid.org/0000-0001-9064-6961)
- Masataka Yokoyama
Institutions
- Chiba University (JP)
- Chiba University Hospital (JP)
- Kazusa DNA Research Institute (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1038/s41467-025-59886-w
- Citations
- 2
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science