High SENP3 Expression Promotes Cell Migration, Invasion, and Proliferation by Modulating DNA Methylation of E-Cadherin in Osteosarcoma

Abstract

SENP3, a sentrin/SUMO2/3-specific protease, is recognized as a transcriptional factor that accumulates under cellular oxidative stress and plays a significant role in the removal of SUMO2/3 modification. In our study, we examined a TCGA dataset and found that the transcripts per million (TPM) value of SENP3 is high in sarcoma, including osteosarcoma (OS). We found that SENP3 was highly expressed in OS cancer tissues when compared with osteofibrous dysplasia tissues. The survival data of SENP3 in TCGA showed that the sarcoma patients with higher SENP3 expression levels showed poor prognosis. In vitro, SENP3 knockdown in OS cancer cells inhibited cell proliferation, migration, and invasion and induced apoptosis. In contrast, SENP3 overexpression reversed these effects. Next, we found that SENP3 inhibited the expression of E-cadherin (E-Cad) by increasing methylation of the E-Cad promoter. Finally, E-Cad expression was increased in the OS cell line MG63 following methylation, and the cell proliferation, migration, and invasion capacity were decreased. In summary, SENP3 played a significant role in OS carcinogenesis and may act as a potential biomarker in the diagnosis and treatment of OS.

SENP3 promotes tumor progression and is a novel prognostic biomarker in triple-negative breast cancer

“…In mice, the deletion of SENP3 in macrophages promotes breast cancer progression and metastasis, according to recently published studies. Moreover, SENP3 may also promote cancer progression by regulating macrophage polarization ( 32 ), and high SENP3 levels are associated with more advanced tumor grades and metastasis as well as poor survival outcomes ( 33 ), meaning that SENP3 may play a role in tumorigenesis and progression. However, the function of SENP3 in TNBC is unclear.…”

Epigenetic Changes Associated with Osteosarcoma: A Comprehensive Review

“…DNA methylation of tumor-suppressing genes is also facilitated directly by other proteins in OS. SENP3, a sentrin/SUMO2/3-specific protease, is upregulated in OS and associated with reduced expression of E-Cadherin (E-Cad) mRNA [ 25 ]. Yang et al demonstrated that the E-cad promoter region featured abnormal methylation of CpG islands in OS patient samples.…”

Cancer-Associated Dysregulation of Sumo Regulators: Proteases and Ligases

“…Mechanistically, overexpressed SENP3 in GC cells targets the EMT-inducing transcription factor forkhead box C2 (FOXC2) for desumoylation, which, in turn, activates expression of the EMT-associated and transendothelial migration-promoting N-cadherin gene ( CDH2 ), among others. In relation to this, it has also been shown that SENP3 overexpression in osteosarcoma cells results in inhibited expression of the epithelium-associated gene CDH1 , which courses with promoter hypermethylation [ 122 ]. Database analysis indicates that in general SENP3 is abundantly expressed in sarcoma and high expression correlates with poor prognosis, being shown in osteosarcoma that SENP3 depletion results in impaired proliferation, migration and invasion, and in enhanced apoptosis.…”

“…Database analysis indicates that in general SENP3 is abundantly expressed in sarcoma and high expression correlates with poor prognosis, being shown in osteosarcoma that SENP3 depletion results in impaired proliferation, migration and invasion, and in enhanced apoptosis. Thus, SENP3 has been suggested as a powerful biomarker for osteosarcoma diagnosis [ 122 ]. SENP3 , in combination with ARID1A and CSMD has also been proposed as an effective prognosis marker in HCC, despite molecular heterogeneity detected in HCC patients [ 118 ].…”