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

• Published in: Oncogene Vol. 40; no. 22; pp. 3870 - 3884
• Main Authors: Li, Ming, Shi, Minke, Hu, Chaoyue, Chen, Baojun, Li, Shufeng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.06.2021; Nature Publishing Group
• Subjects: 38/44; 38/61; 38/71; 38/77; 45/41; 45/61; 631/67/1612/1350; 631/67/1857; 64/60; 82/1; 82/80; Adenocarcinoma; Aged; Animals; Apoptosis; Cancer; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Biology; Cell Line; Cell Movement - physiology; Cell Proliferation - physiology; Development and progression; Disease Progression; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Forkhead protein; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Genetic aspects; Genetic transcription; Health aspects; Heterografts; Homology; Human Genetics; Humans; Internal Medicine; Leucine zipper proteins; Lung cancer; Lung cancer, Non-small cell; Lung carcinoma; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Nude; Non-small cell lung carcinoma; Oncology; Oncology, Experimental; Post-translation; Post-translational modification; Proteins; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Survival Rate; Transcription factors; Tumors; Ubiquitin-proteasome system; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Zinc finger proteins; China
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01816-3

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.