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MALAT1 modulated FOXP3 ubiquitination then affected GINS1 transcription and drived NSCLC proliferation

Oncogene volume 40, pages 3870–3884 (2021)Cite this article

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Abstract

An increasing number of studies have shown that long-noncoding RNAs (lncRNAs) are involved in the post-translational modifications (PTMs) of protein in a variety of tumors. However, little is known about the exact regulation mechanism of lncRNAs in regulating PTMs in non-small-cell lung carcinoma (NSCLC) proliferation. Metastasis-associated lung adenocarcinoma transcript1 (MALAT1) and GINS complex subunit 1(GINS1) both were upregulated and promoted proliferation progression in NSCLC. In this study, the clinicopathologic significance of MALAT1 and GINS1 in NSCLC was investigated, a positive correlation in their expression was found. The silencing of MALAT1 decreased GINS1 expression and inhibited NSCLC proliferation in vitro and in vivo. The upregulation of GINS1 reversed NSCLC proliferation inhibited by MALAT1 knockdown. FOXP3 (forkhead box protein 3) was identified as the critical transcription factor for GINS1 transcription. In addition, MALAT1 could stabilize FOXP3 by binding to zinc finger (ZF) domain and leucine zipper (LZ) domain of FOXP3. Interestingly, these two domains were also interaction domains for FOXP3 binding with E3 ligase STUB1 (STIP1 homology and U-box containing protein 1). In this way, MALAT1 masked the protein-interacting domain, and inhibited FOXP3 ubiquitination by STUB1. Together, our results identified a novel regulatory axis of MALAT1-FOXP3-GINS1, and demonstrated that MALAT1 played an important modulatory role in PTM of FOXP3 which affects GINS1 transcription and drives proliferation character in NSCLC.

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Fig. 1: MALAT1 and GINS1 expression are both upregulated in NSCLC samples and are closely related to NSCLC progression.
Fig. 2: Stable knockdown of MALAT1 represses GINS1 expression and inhibits NSCLC proliferation in vitro and in vivo.
Fig. 3: GINS1 is critical for MALAT1-mediated NSCLC cell proliferation.
Fig. 4: FOXP3 is essential for the MALAT1-mediated GINS1 transcription.
Fig. 5: MALAT1 stabilizes FOXP3 through inhibiting the ubiquitination of FOXP3.
Fig. 6: MALAT1 stabilizes FOXP3 by blocking FOXP3 interaction with E3 ligase STUB1 in NSCLC cells.
Fig. 7: The PTM model of MALAT1 involved in target protein modification was proposed.

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  1. Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Department of Biochemistry and Molecular Biology, Medical School of Southeast University, Nanjing, China

    Ming Li & Shufeng Li

  2. Department of Thoracic and Cardiovascular Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China

    Minke Shi, Chaoyue Hu & Baojun Chen

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Li, M., Shi, M., Hu, C. et al. MALAT1 modulated FOXP3 ubiquitination then affected GINS1 transcription and drived NSCLC proliferation. Oncogene 40, 3870–3884 (2021). https://doi.org/10.1038/s41388-021-01816-3

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