SUMO‑specific protease 2 (SENP2) functions as a tumor suppressor in osteosarcoma via SOX9 degradation

Pei, Hong; Chen, Liang; Liao, Quan-ming; Wang, Ke‐Jun; Chen, Shunguang; Liu, Zheng‐Jie; Zhang, Zhi‐Cai

doi:10.3892/etm.2018.6838

Cited by 13 publications

(22 citation statements)

References 25 publications

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“…However, high expression has been associated with better prognosis in some cancer types. Downregulated expression levels in cancer tissues have consistently been reported for SENP2 [52][53][54][55][56][57] and PIAS2 [58][59][60]. The prognostic value of a single SUMO machinery component can also vary between cancer (sub)types, and, e.g., the value for PC2 [61,62] and PIAS4 [63,64] as prognostic biomarkers in breast cancer and for PIAS3 [65,66] in mesothelioma remains ambiguous (Table 1).…”

Section: Altered Expression and Prognostic Significance Of Sumo Pathway In Cancermentioning

confidence: 99%

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Kukkula

Ojala

Mendez

et al. 2021

Cancers

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SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.

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Section: Altered Expression and Prognostic Significance Of Sumo Pathway In Cancermentioning

confidence: 99%

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Kukkula

Ojala

Mendez

et al. 2021

Cancers

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“…15 As we know, SOX9 is an important member of the SOX family affecting multiple cellular processes. 16–18 SOX9 could activate downstream Akt activity. 19 SOX9 could inhibit apoptosis and inflammatory response by activating Akt /GSK3β pathway, and protect MRC5 of fetal lung fibroblasts from LPS-induced injury.…”

Section: Discussionmentioning

confidence: 99%

ZNF219 protects human lens epithelial cells against H₂O₂-induced injury via targeting SOX9 through activating AKT/GSK3β pathway

2021

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Opacity of the lens caused by cataracts could lead to severe visual impairment and even blindness. Oxidative stress caused by exposure of lens epithelial cells to hydrogen peroxide (H2O2) can lead to DNA damage and impair cell function. Therefore, how to prevent lens epithelial cells from being harmed by H2O2 is an urgent problem. The ZNF219 gene belongs to the Kruppel like zinc finger gene family, which is involved in a variety of biological processes. In this study, we found the low expression of ZNF219 in H2O2-induced HLE-B3 cells. We further noticed ZNF219 could improve the survival rate of H2O2-induced HLE-B3 cells, and inhibit the apoptosis and oxidative stress response. Mechanically, ZNF219 protected human lens epithelial cells against H2O2-induced injury via targeting SOX9 through activating AKT/GSK3β pathway. We therefore thought ZNF219 was a key protective protein in the oxidative damage of human lens epithelial cells and the pathogenesis of cataract.

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“…SENP2 is a tumor suppressor; its expression is silenced in osteosarcoma 37 . Similarly, we found SENP2 expression silenced in bortezomib resistant MM.…”

Section: Discussionmentioning

confidence: 99%

Silencing of SENP2 in Multiple Myeloma Induces Bortezomib Resistance by Activating NF-κB Through the Modulation of IκBα Sumoylation

Xie

Wang

et al. 2020

Sci Rep

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The proteasome inhibitor bortezomib is the most successfully applied chemotherapeutic drug for treating multiple myeloma. However, its clinical efficacy reduced due to resistance development. The underlying molecular mechanisms of bortezomib resistance are poorly understood. In this study, by combining in silico analysis and sgRNA library based drug resistance screening assay, we identified SENP2 (Sentrin/SUMO-specific proteases-2) as a bortezomib sensitive gene and found its expression highly downregulated in bortezomib resistant multiple myeloma patient's samples. Furthermore, down regulation of SENP2 in multiple myeloma cell line RPMI8226 alleviated bortezomib induced cell proliferation inhibition and apoptosis, whereas, overexpression of SENP2 sensitized these cells to bortezomib treatment. We further demonstrate that knockdown of SENP2 in RPMI8226 cells increased SUMO2 conjugated IκBα that resulted in the activation of NF-κB. Taken together, we report that silencing of SENP2 and consequent activation of NF-κB through the modulation of IκBα sumoylation as a novel mechanism inducing bortezomib resistance in multiple myeloma. Multiple myeloma (MM) is a malignant plasma cell tumor that account for 12% of blood malignant tumors, which is the second most commonly diagnosed hematologic malignancy 1. Despite applying multiple therapeutic drugs such as, proteasome inhibitor bortezomib 2 and immunomodulator thalidomide 3 , the median MM patient survival was only slightly improved from 3-5 years to 5-7 years 4. Moreover, MM is still featured as a recurrence and insensitive to treatment due to drug resistance development 5. The bortezomib is the first class of proteasome inhibitor approved for the treatment of MM. Bortezomib is a dipeptidyl boronic acid that reversibly binds to chymotrypsin-like catalytic subunit of 20 S proteasome and inhibits its activity 6. Proteasome plays a critical role in cellular homeostasis by degrading unwanted cellular proteins 7. The imbalance between synthesis and degradation of proteins arises due to proteasome inhibition results in the accumulation of regulatory proteins causing endoplasmic reticulum stress and activation of the unfolded protein response leading to induction of apoptosis in malignant cells via multiple mechanisms 8,9 .

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SUMO‑specific protease 2 (SENP2) functions as a tumor suppressor in osteosarcoma via SOX9 degradation

Cited by 13 publications

References 25 publications

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

ZNF219 protects human lens epithelial cells against H₂O₂-induced injury via targeting SOX9 through activating AKT/GSK3β pathway

Silencing of SENP2 in Multiple Myeloma Induces Bortezomib Resistance by Activating NF-κB Through the Modulation of IκBα Sumoylation

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SUMO‑specific protease 2 (SENP2) functions as a tumor suppressor in osteosarcoma via SOX9 degradation

Cited by 13 publications

References 25 publications

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

ZNF219 protects human lens epithelial cells against H2O2-induced injury via targeting SOX9 through activating AKT/GSK3β pathway

Silencing of SENP2 in Multiple Myeloma Induces Bortezomib Resistance by Activating NF-κB Through the Modulation of IκBα Sumoylation

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ZNF219 protects human lens epithelial cells against H₂O₂-induced injury via targeting SOX9 through activating AKT/GSK3β pathway