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GIAT4RA functions as a tumor suppressor in non-small cell lung cancer by counteracting Uchl3–mediated deubiquitination of LSH

Oncogene volume 38, pages 7133–7145 (2019)Cite this article

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Abstract

Elucidating mechanisms in tumor suppressors and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, the interplay between long intergenic non-coding RNAs (lncRNAs) and chromatin remodeling remains unclear. Here, we showed that GIAT4RA, a poorly characterized lncRNA LOC102723729, was significantly decreased in lung cancer cells and tissues; while no association was observed with clinical risk factors, expression was linked with clinical stage and lymphatic metastasis. Higher expression of GIAT4RA was linked with overall survival in NSCLC. GIAT4RA inhibited many characteristics of tumorigenesis including cell growth, clonal formation, migration and invasion, epithelial–mesenchymal transition, tumor sphere and tumor growth in vivo. Mechanistically, GIAT4RA was essential for the degradation of chromatin modifier lymphoid-specific helicase (LSH) by counteracting the deubiquintination in proteasome pathway by binding to 227-589 AA of LSH. GIAT4RA interfered with ubiquitin hydrolase Uchl3-mediated interaction and stabilization of LSH. LSH knockdown rescued GIAT4RA-promoted features, and LSH overexpression prevented GIAT4RA-induced phenotypes. Taken together, lncRNA GIAT4RA plays a critical role in NSCLC adenocarcinoma as a ubiquitination regulator and tumor suppressor.

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Acknowledgements

We thank a lot to Prof. Lingqiang Zhang (State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine) for providing plasmids.

Funding

This work was supported by the National Natural Science Foundation of China (81672787 [YT], 81672991 and 81874139 [SL], 81728014 [QY], 81672308 [XW]), the National Basic Research Program of China (2015CB553903 [YT]), and the Fundamental Research Funds for the Central Universities (2017zzts828 [RY] and 2017zzts206 [NL]).

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  1. These authors contributed equally: Rui Yang, Na Liu

Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, Hunan, 410078, China

    Rui Yang, Na Liu, Ling Chen, Yiqun Jiang, Ying Shi, Chao Mao, Yating Liu, Min Wang, Weiwei Lai, Haosheng Tang, Menghui Gao, Ya Cao & Yongguang Tao

  2. Key Laboratory of Carcinogenesis of Ministry of Health, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China

    Rui Yang, Na Liu, Ling Chen, Yiqun Jiang, Ying Shi, Chao Mao, Yating Liu, Min Wang, Weiwei Lai, Haosheng Tang, Menghui Gao, Ya Cao & Yongguang Tao

  3. Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Yiqun Jiang & Desheng Xiao

  4. Department of Thoracic Surgery, Hunan Key Laboratory of Tumor Models and Individualized Medicine, Second Xiangya Hospital, Central South University, Changsha, China

    Xiang Wang, Wenliang Liu, Fenglei Yu & Yongguang Tao

  5. Shanghai Institute of Material Medica, Chinese Academy of Sciences (CAS), 555 Zu Chongzhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China

    Hu Zhou

  6. Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Can-e Tang & Shuang Liu

  7. Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, USA

    Qin Yan

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Contributions

In this report, YT, QY, and SL designed the experiments and drafted the paper; RY, NL, LC, YJ, YS, YL, CM, MW, WL, HT, and MG performed the experiments. DX, XW, HZ, SL, CT and WL were responsible for sample collection and data analysis; SL, WL, FY, YC, QY, and YT discussed and revised the paper. YT was the originator of the concept of this report and wrote and approved the paper. All of the authors approved this paper.

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Correspondence to Shuang Liu or Yongguang Tao.

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This study was conducted at the Cancer Research Institute, Central South University, Hunan, China. All of the protocols were reviewed and approved by the Joint Ethics Committee of the Central South University Health Authority and performed in accordance with national guidelines.

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Yang, R., Liu, N., Chen, L. et al. GIAT4RA functions as a tumor suppressor in non-small cell lung cancer by counteracting Uchl3–mediated deubiquitination of LSH. Oncogene 38, 7133–7145 (2019). https://doi.org/10.1038/s41388-019-0909-0

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