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Oncogenic SNORD12B activates the AKT-mTOR-4EBP1 signaling in esophageal squamous cell carcinoma via nucleus partitioning of PP-1α

Oncogene volume 40, pages 3734–3747 (2021)Cite this article

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Abstract

Esophageal cancer is a complex malignancy and the sixth leading cause of cancer death worldwide. In Eastern Asia including China, about 90% of all incident cases have esophageal squamous cell carcinoma (ESCC). Mounting evidence elucidates that aberrant expression of various non-coding RNAs (ncRNAs) contributes to ESCC progression, but it remains unclear how small nucleolar RNAs (snoRNAs) are involved in ESCC development. We systemically screened clinically relevant snoRNAs in ESCC via integrative analyses of The Cancer Genome Atlas (TCGA) data and validation in ESCC tissues. We found that snoRNA SNORD12B was one of the most evidently upregulated snoRNAs in ESCC specimens and its high expression was significantly associated with poor prognosis of patients. SNORD12B profoundly promoted proliferation, migration, invasion, and metastasis of ESCC cells in vitro and in vivo, indicating its oncogene nature. In particular, SNORD12B could interact with PP-1α, one of the three catalytic subunits of serine/threonine protein phosphatase 1, which is a major phosphatase that directly dephosphorylates AKT to suppress its activation. Interestingly, high levels of SNORD12B in ESCC cells could break interactions between 14-3-3ζ and PP-1α, abolish the retention of PP-1α in the cytosol by 14-3-3ζ and relocate PP-1α from the cytosol to the nucleus. This led to sequestered PP-1α in the nucleus, enhanced phosphorylation of AKT in the cytosol, activated AKT-mTOR-4EBP1 signaling, and, thus, ESCC progression. These insights would improve our understanding of how snoRNAs contribute to tumorigenesis and highlight the potential of snoRNAs as future therapeutic targets against cancers.

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Fig. 1: SNORD12B was one of the most significantly upregulated snoRNAs in ESCC specimens.
Fig. 2: SnoRNA SNORD12B accelerated malignant proliferation of ESCC cells in vitro and in vivo.
Fig. 3: SnoRNA SNORD12B promoted metastasis of ESCC cells in vitro and in vivo.
Fig. 4: SnoRNA SNORD12B interacted with PP-1α and promoted shuttling of PP-1α to nucleus.
Fig. 5: SNORD12B activated the AKT-mTOR-4EBP1 signaling.
Fig. 6: In normal cells,14-3-3ζ binds to PP-1α and cause retention of PP-1α in the cytosol.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31671300, 31871306); Taishan Scholars Program of Shandong Province (tsqn20161060); Program of Science and Technology for the youth innovation team in universities of Shandong Province (2020KJL001); Medical and Health Science and Technology Development Plan of Shandong Province (2019WS202); Youth Foundation Programs of Shandong Academy of Medical Sciences (2018-28). The authors would like to thank the many individuals who participated in the study.

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  1. Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China

    Baoqing Tian, Jiandong Liu, Nasha Zhang, Yemei Song, Hui Hua & Ming Yang

  2. Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China

    Yeyang Xu, Mengyu Xie, Bowen Wang, Yue Shen & Yankang Li

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Tian, B., Liu, J., Zhang, N. et al. Oncogenic SNORD12B activates the AKT-mTOR-4EBP1 signaling in esophageal squamous cell carcinoma via nucleus partitioning of PP-1α. Oncogene 40, 3734–3747 (2021). https://doi.org/10.1038/s41388-021-01809-2

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