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Long non-coding RNA TILR constitutively represses TP53 and apoptosis in lung cancer

Oncogene volume 42, pages 364–373 (2023)Cite this article

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Abstract

Non-coding RNAs have an integral regulatory role in numerous functions related to lung cancer development. Here, we report identification of a novel lncRNA, termed TP53-inhibiting lncRNA (TILR), which was found to function as a constitutive negative regulator of p53 expression, including activation of downstream genes such as p21 and MDM2, and induction of apoptosis. A proteomic search for TILR-associated proteins revealed an association with PCBP2, while the mid-portion of TILR was found to be required for both PCBP2 and p53 mRNA binding. In addition, depletion of PCBP2 resulted in phenocopied effects of TILR silencing. TILR was also shown to suppress p53 expression in a post-transcriptional manner, as well as via a positive feedback loop involving p53 and Fanconi anemia pathway genes. Taken together, the present findings clearly demonstrate that TILR constitutively inhibits p53 expression in cooperation with PCBP2, thus maintaining p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.

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Fig. 1: Identification of TP53-inhibiting lncRNA (TILR).
Fig. 2: TILR suppresses p53 transcriptional activity.
Fig. 3: PCBP2 associates with TILR.
Fig. 4: PCBP2 represses p53 transcriptional response.
Fig. 5: TILR and PCBP2 control p53 translation.
Fig. 6: TILR suppresses p53 protein stability and ubiquitination.
Fig. 7: TILR regulates Fanconi anemia pathway to suppress p53 protein.

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Data availability

The microarray data generated in this study have been deposited in the NCBI Gene Expression Omnibus database under the accession code GSE180940 and GSE180944.

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Acknowledgements

We thank Naoe Hotta and Keiko Kano for assistance with data collection, as well as Sebastian Griesing and Atsuko Niimi for the helpful discussion. This work was supported in part by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, Grants-in-Aid for Scientific Research (A) and (C) from the Japan Society for the Promotion of Science, Takeda Science Foundation, and a grant from the Princess Takamatsu Cancer Research Fund.

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Author notes

  1. These authors contributed equally: Mika Iwai, Taisuke Kajino.

Authors and Affiliations

  1. Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan

    Mika Iwai, Taisuke Kajino, Kiyoshi Yanagisawa, Hisanori Isomura, Yukako Shimada, Motoshi Suzuki & Takashi Takahashi

  2. Division of Molecular Diagnostics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan

    Taisuke Kajino, Hisanori Isomura, Yukako Shimada & Ayumu Taguchi

  3. Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, 461-8673, Japan

    Masahiro Nakatochi

  4. Department of Molecular and Cancer Medicine, Faculty of Pharmacy, Meijo University, Nagoya, 468-8502, Japan

    Kiyoshi Yanagisawa

  5. Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan

    Yasuyuki Hosono

  6. Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan

    Yasuyuki Hosono

  7. Department of Molecular Oncology, School of Medicine, Fujita Health University, Toyoake, 470-1192, Japan

    Motoshi Suzuki

  8. Division of Advanced Cancer Diagnostics, Department of Cancer Diagnostics and Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, 464-8681, Japan

    Ayumu Taguchi

  9. Aichi Cancer Center, Nagoya, 464-8681, Japan

    Takashi Takahashi

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Contributions

MI, TK, and TT conceived the project. MI, TK, KY, YH, HI, and YS performed the experiments. MI, TK, KY, MS, AT, and TT analyzed the data. TK and MN performed the informatics analysis. MI, TK, and TT wrote the paper, with input from all authors. TT supervised the project.

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Correspondence to Takashi Takahashi.

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Iwai, M., Kajino, T., Nakatochi, M. et al. Long non-coding RNA TILR constitutively represses TP53 and apoptosis in lung cancer. Oncogene 42, 364–373 (2023). https://doi.org/10.1038/s41388-022-02546-w

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