lncRNA GMDS-AS1 Restrains Lung Adenocarcinoma Progression Via Recruiting TAF15 Protein to Stabilize SIRT1 mRNA

Abstract

Aim: To explore the roles of GMDS-AS1 in the epithelial–mesenchymal transition (EMT) of lung adenocarcinoma (LUAD). Materials & methods: Cell functions were detected by flow cytometry, cell counting kit-8, wound healing assays and transwell assays. RNA immunoprecipitation and pull-down assays were applied for determining the interaction among GMDA-AS1, TAF15 and SIRT1. A subcutaneous xenograft model was established. Results: GMDS-AS1 downregulation was associated with poor survival of LUAD patients. GMDS-AS1 repressed malignant phenotypes, tumor growth and EMT in vitro and in vivo. Mechanically, GMDS-AS1 recruited TAF15 protein to stabilize SIRT1 mRNA and thereby deacetylated p65 and reduced the recruitment of p65 to MMP-9 promoter, thus inhibiting MMP-9 expression. Conclusion: GMDS-AS1 represses EMT by recruiting TAF15 protein to stabilize SIRT1 mRNA and deacetylate p65, thus restraining LUAD progression.

Plain language summary

GMDS-AS1, a novel lncRNA, is involved in the progression of lung adenocarcinoma (LUAD), but the mechanism by which GMDS-AS1 regulates LUAD progression remains largely unknown. This study found that GMDS-AS1 was downregulated in LUAD patients, and its low expression was associated with advanced metastasis and poor survival. Overexpression of GMDS-AS1 significantly impaired tumor cell viability, proliferation, migration, invasion and epithelial–mesenchymal transition but enhanced apoptosis. In addition, GMDS-AS1 repressed tumor growth in mice. GMDS-AS1 functioned as a tumor suppressor in LUAD by recruiting TAF15 protein to stabilize SIRT1 mRNA and deacetylate p65, thus decreasing the recruitment of p65 to MMP-9 promoter. These findings have uncovered a novel mechanism underlying LUAD progression and suggested potential prognostic biomarkers and therapeutic targets.

Tweetable abstract

GMDS-AS1 represses the progression of lung adenocarcinoma, and its low expression in lung adenocarcinoma patients indicates poor prognosis.

Graphical abstract

Keywords::

• acetylation
• EMT
• GMDS-AS1
• lung adenocarcinoma
• p65
• SIRT1
• TAF15

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2022-0432

Financial & competing interests disclosure

This work was supported by the National Natural Science Foundation of China: no. 82003065; Changsha Natural Science Foundation: no. kp2014200; Hunan Natural Science Foundation: no. 2021JJ40293; Outstanding Youth Program of Hunan Provincial Department of Education: no, 20B373. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

All patients provided written informed consent, and the Ethics Committee of Hunan Provincial People’s Hospital, The First Affiliated of Human Normal University, approved our study. Animal procedures were approved by the Animal Care and Use Committee of Hunan Provincial People’s Hospital, The First Affiliated of Human Normal University.

Data sharing statement

The datasets generated during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China: no. 82003065; Changsha Natural Science Foundation: no. kp2014200; Hunan Natural Science Foundation: no. 2021JJ40293; Outstanding Youth Program of Hunan Provincial Department of Education: no, 20B373. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.