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PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells.

ABSTRACT: Transforming growth factor β (TGFβ) signaling plays an important role in regulating tumor malignancy, including in non-small cell lung cancer (NSCLC). The major biological responses of TGFβ signaling are determined by the effector proteins SMAD2 and SMAD3. However, the regulators of TGFβ-SMAD signaling are not completely revealed yet. Here, we showed that the scaffolding protein PDLIM5 (PDZ and LIM domain protein 5, ENH) critically promotes TGFβ signaling by maintaining SMAD3 stability in NSCLC. First, PDLIM5 was highly expressed in NSCLC compared with that in adjacent normal tissues, and high PDLIM5 expression was associated with poor outcome. Knockdown of PDLIM5 in NSCLC cells decreased migration and invasion in vitro and lung metastasis in vivo In addition, TGFβ signaling and TGFβ-induced epithelial-mesenchymal transition was repressed by PDLIM5 knockdown. Mechanistically, PDLIM5 knockdown resulted in a reduction of SMAD3 protein levels. Overexpression of SMAD3 reversed the TGFβ-signaling-repressing and anti-migration effects induced by PDLIM5 knockdown. Notably, PDLIM5 interacted with SMAD3 but not SMAD2 and competitively suppressed the interaction between SMAD3 and its E3 ubiquitin ligase STUB1. Therefore, PDLIM5 protected SMAD3 from STUB1-mediated proteasome degradation. STUB1 knockdown restored SMAD3 protein levels, cell migration, and invasion in PDLIM5-knockdown cells. Collectively, our findings indicate that PDLIM5 is a novel regulator of basal SMAD3 stability, with implications for controlling TGFβ signaling and NSCLC progression.

SUBMITTER: Shi Y

PROVIDER: S-EPMC7535919 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIt is clearly necessary to discover prognostic biomarkers to identify stage I patients at risk of recurrence and give them timely postoperative treatment.Materials and methodsData of stage I lung adenocarcinoma were retrieved from four gene series in Gene Expression Omnibus (GEO) database (GSE50081, GSE30219, GSE37745, and GSE13213). Partek Genomics Suite software was used to identify survival-related genes for finding candidate indicators for early-stage patients at risk of recurrence. Differential expression of MTBP (MDM2 binding protein) in early-stage lung adenocarcinoma tissues was determined by immunohistochemical staining. The effects of MTBP interference expression and overexpression on viability, migration, and invasion capacity of lung cells were evaluated using Cell Counting Kit-8, wound healing, and Transwell assays. The tumor growth and lung metastasis in vivo were observed in chick embryo chorioallantoic membrane model. Human Exon 2.0 ST Array was used to analyze downstream regulation genes of MTBP in lung cancer cells. Involvement of ZEB2 and epithelial-mesenchymal transition (EMT) markers was investigated by Western blot.ResultsBy mining GEO database, we identified MTBP as a poor prognostic indicator of stage I lung adenocarcinomas. In addition, increased expression of MTBP was also associated with poor survival in our early-stage lung adenocarcinoma cohort. Further experiment suggested that knockdown of MTBP suppressed the migration and invasion of A549 and H1975 cells in vitro and in vivo, whereas overexpression of MTBP in HCC827 and PC9 cells promoted the migration and invasion in vitro and in vivo. Furthermore, ZEB2 upregulation directly activated EMT to mediate the downstream effects of MTBP involved in lung cancer cells metastasis.ConclusionMTBP is an independent indicator for poor prognosis in stage I lung adenocarcinomas and might promote the aggressive phenotype of non-small-cell lung cancer by inducing the EMT process through upregulating ZEB2 expression.

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PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells.

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