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RUNX1-IT1 acts as a scaffold of STAT1 and NuRD complex to promote ROS-mediated NF-κB activation and ovarian cancer progression

Oncogene volume 43, pages 420–433 (2024)Cite this article

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Abstract

Dysregulated expression of long-stranded non-coding RNAs is strongly associated with carcinogenesis. However, the precise mechanisms underlying their involvement in ovarian cancer pathogenesis remain poorly defined. Here, we found that lncRNA RUNX1-IT1 plays a crucial role in the progression of ovarian cancer. Patients with high RUNX1-IT1 expression had shorter survival and poorer outcomes. Notably, knockdown of RUNX1-IT1 suppressed the proliferation, migration and invasion of ovarian cancer cells in vitro, and reduced the formation of peritoneum metastasis in vivo. Mechanistically, RUNX1-IT1 bound to HDAC1, the core component of the NuRD complex, and STAT1, acting as a molecular scaffold of the STAT1 and NuRD complex to regulate intracellular reactive oxygen homeostasis by altering the histone modification status of downstream targets including GPX1. Consequently, RUNX1-IT1 activated NF-κB signaling and altered the biology of ovarian cancer cells. In conclusion, our findings demonstrate that RUNX1-IT1 promotes ovarian malignancy and suggest that targeting RUNX1-IT1 represents a promising therapeutic strategy for ovarian cancer treatment.

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Fig. 1: Upregulation of RUNX1-IT1 correlates with metastasis and poor prognosis in ovarian cancer.
Fig. 2: RUNX1-IT1 promotes the proliferation and metastasis of ovarian cancer cells.
Fig. 3: RUNX1-IT1 physically interacts with the NuRD complex in ovarian cancer cells.
Fig. 4: RUNX1-IT1 regulates downstream targets by coordinating the genome-wide localization of NuRD complex.
Fig. 5: The regulation of GPX1 by the RUNX1-IT1/NuRD complex is mediated by STAT1.
Fig. 6: RUNX1-IT1-STAT1-NuRD complex regulates reactive oxygen species levels to activate the NF-κB signaling pathway and promotes metastasis.
Fig. 7: RUNX1-IT1 presents a promising therapeutic target for ovarian cancer.
Fig. 8: Proposed model of the mechanism underlying the role of RUNX1-IT1 in the progression of ovarian cancer.

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Data availability

The data generated in this study are available within the article and its supplementary information files. The raw data generated in this study are publicly available in Gene Expression Omnibus (GEO) at GSE224495 and GSE245778.

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Funding

This research was funded by the National Key R&D Program of China (2021YFC2501000, 2020YFA0803300), the National Natural Science Foundation of China (82030089, 82188102), the CAMS Innovation Fund for Medical Sciences (2021–1-I2M-018, 2021-I2M-1-067, 2022-I2M-2-001).

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Author notes

  1. Qingyu Luo & Xiaowei Wu

    Present address: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA

  2. These authors contributed equally: Xiao Yu, Pengfei Zhao.

Authors and Affiliations

  1. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Xiao Yu, Pengfei Zhao, Qingyu Luo, Xiaowei Wu, Yabing Nan, Shi Liu, Wenyan Gao & Zhihua Liu

  2. Department of Gynecological Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Yating Wang & Bin Li

  3. Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China

    Zhumei Cui

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Contributions

XY and PZ contributed equally to this work. ZL and ZC conceived the ideas and supervised the research. XY and PZ performed most of the experiments, analyzed the data and drafted the manuscript with assistance from ZL and ZC. WG performed the bioinformatics analyses. QL, XW, YW, and BL collected clinical samples. SL and YN assisted with animal studies. All authors reviewed the manuscript and agreed to the published version of the manuscript.

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Correspondence to Zhihua Liu or Zhumei Cui.

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Yu, X., Zhao, P., Luo, Q. et al. RUNX1-IT1 acts as a scaffold of STAT1 and NuRD complex to promote ROS-mediated NF-κB activation and ovarian cancer progression. Oncogene 43, 420–433 (2024). https://doi.org/10.1038/s41388-023-02910-4

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