Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis
Journal
Journal of Experimental and Clinical Cancer Research
Journal Volume
38
Journal Issue
1
Date Issued
2019
Author(s)
Hung P.-F.
Hong, T.-M.
Chang C.-C.
Hung C.-L.
Hsu Y.-L.
Chang G.-C.
Abstract
Background: The Slug-E-cadherin axis plays a critical role in non-small-cell lung cancers (NSCLCs) where aberrant upregulation of Slug promotes cancer metastasis. Now, the post-translational modifications of Slug and their regulation mechanisms still remain unclear in lung cancer. Hence, exploring the protein linkage map of Slug is of great interest for investigating the scenario of how Slug protein is regulated in lung cancer metastasis. Methods: The Slug associated proteins, Ubc9 and SUMO-1, were identified using yeast two-hybrid screening; and in vitro SUMOylation assays combined with immunoprecipitation and immunoblotting were performed to explore the detail events and regulations of Slug SUMOylation. The functional effects of SUMOylation on Slug proteins were examined by EMSA, reporter assay, ChIP assay, RT-PCR, migration and invasion assays in vitro, tail vein metastatic analysis in vivo, and also evaluated the association with clinical outcome of NSCLC patients. Results: Slug protein could interact with Ubc9 and SUMO-1 and be SUMOylated in cells. Amino acids 130-212 and 33-129 of Slug are responsible for its binding to Ubc9 and protein inhibitor of activated STAT (PIAS)y, respectively. SUMOylation could enhance the transcriptional repression activity of Slug via recruiting more HDAC1, resulting in reduced expression of downstream Slug target genes and enhanced lung cancer metastasis. In addition, hypoxia could increase Slug SUMOylation through attenuating the interactions of Slug with SENP1 and SENP2. Finally, high expression Slug and Ubc9 levels were associated with poor overall survival among NSCLC patients. Conclusions: Ubc9/PIASy-mediated Slug SUMOylation and subsequent HDAC1 recruitment may play a crucial role in hypoxia-induced lung cancer progression, and these processes may serve as therapeutic targets for NSCLC. ? 2019 The Author(s).
SDGs
Other Subjects
histone deacetylase 1; messenger RNA; protein inhibitor of activated STAT; protein Ubc9; proteinase; SENP1 protein; SENP2 protein; SUMO 1 protein; transcription factor Slug; unclassified drug; adult; animal experiment; animal model; animal tissue; Article; cancer prognosis; cell hypoxia; cell invasion; cell migration; chromatin; controlled study; female; human; human cell; lung cancer; major clinical study; male; metastasis; non small cell lung cancer; nonhuman; overall survival; priority journal; protein protein interaction; sumoylation; transcription regulation; transcriptional repression; complication; genetic transfection; genetics; lung tumor; metastasis; pathology; sumoylation; tumor cell line; Cell Hypoxia; Cell Line, Tumor; Humans; Lung Neoplasms; Neoplasm Metastasis; Sumoylation; Transfection
Publisher
BioMed Central Ltd.
Type
journal article