Abstract
Long noncoding RNAs (lncRNAs) are dysregulated in different cancer types, and thus have emerged as important regulators of the initiation and progression of human cancers. However, the biological functions and the underlying mechanisms responsible for their functions in gastric cancer (GC) remain poorly understood. Here, by lncRNA microarray, we identified 1414 differentially expressed lncRNAs, among which THAP7-AS1 was significantly upregulated in GC tissues compared with non-tumorous gastric tissues. High expression of THAP7-AS1 was correlated with positive lymph node metastasis and poorer prognosis. SP1, a transcription factor, could bind directly to the THAP7-AS1 promoter region and activate its transcription. Moreover, the m6A modification of THAP7-AS1 by METTL3 enhanced its expression depending on the “reader” protein IGF2BP1-dependent pathway. THAP7-AS1 promoted GC cell progression. Mechanistically, THAP7-AS1 interacted with the 1-50 Amino Acid Region (nuclear localization signal) of CUL4B through its 1-442 nt Sequence, and it promoted interaction between nuclear localization signal (NLS) and importin α1, and improved the CUL4B protein entry into the nucleus, repressing miR-22-3p and miR-320a expression by CUL4B-catalyzed H2AK119ub1 and the EZH2-mediated H3K27me3, subsequently activating PI3K/AKT signaling pathway to promote GC progression. Moreover, LV-sh-THAP7-AS1 treatment could suppress GC growth, invasion and metastasis, indicating that THAP7-AS1 may act as a promising molecular target for GC therapies. Taken together, our results show that THAP7-AS1, transcriptionally activated by SP1 and then modified by METTL3-mediated m6A, exerts oncogenic functions, by promoting interaction between NLS and importin α1 and then improving the CUL4B protein entry into the nucleus to repress the transcription of miR-22-3p and miR-320a.
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Data availability
All data generated or analyzed during this study are included in this published article and its supplementary information files. Microarray data were deposited in NCBI Gene Expression Omnibus (GEO, GSE150539).
Change history
09 July 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41418-024-01335-0
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Acknowledgements
We thank all the participants for their contributions to the study.
Funding
This study was supported by the National Natural Science Foundation of China (Grant No. 81672842, 82072665 and 31671427), the Taishan Scholars Program of Shandong Province (Grant No. ts201511096), Major projects of transformation of new and old kinetic energy in Shandong Province, Natural Science Foundation of Shandong Province (Grant No. ZR2020QH223) and Postdoctoral Innovation Project of Shandong Province (No.202001006).
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P.G. performed the conception and design of this manuscript. H.-T.L., Y.-X.Z., S.L., G.-H.Z., X.-Y.G., and W.-J.Z. collected clinical tumor samples. H.-T.L. and P.G. performed data analysis and interpretation. H.-T.L. and P.G. performed the manuscript writing. R.-R.M. provides experiment guidance. All authors were involved in writing the paper and had final approval of the final manuscript.
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Clinical tissue samples were obtained from Qilu Hospital and Shandong Provincial Hospital. This study was approved by the Medical Ethics Committee of the Shandong University and performed in accordance with the Declaration of Helsinki. All participants have informed consent and their privacy has been fully protected. All of the animal experiments were conducted according to the Guidelines for Animal Health and Use (Ministry of Science and Technology, China, 2006). Animal experiments were approved by the Committee for Animal Protection of Shandong University.
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The original online version of this article was revised: Mistakenly copied the PIK3CD strip of Figure 5A by combining the pictures.
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Liu, HT., Zou, YX., Zhu, Wj. et al. lncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus. Cell Death Differ 29, 627–641 (2022). https://doi.org/10.1038/s41418-021-00879-9
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DOI: https://doi.org/10.1038/s41418-021-00879-9
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