Inhibition of SUMO-specific protease 1 induces apoptosis of astroglioma cells by regulating NF-κB/Akt pathways

doi:10.1016/j.gene.2016.09.040

Gene

Volume 595, Issue 2, 31 December 2016, Pages 175-179

https://doi.org/10.1016/j.gene.2016.09.040 Get rights and content

Highlights

•
Expression of SENP1 is positively correlated with the astroglioma malignant degree.
•
NF-κB, Akt and p38 anti-apoptosis signaling pathways are activated in astrocytoma.
•
Inhibition of SENP1 induces apoptosis.
•
SENP1 inhibition promotes cell apoptosis by regulating NF-κB/Akt signaling pathways.

Abstract

SUMO-specific protease 1 (SENP1) is an important regulation protease in the protein desumoylation, which was shown to have a prooncogenicrole in many types of cancer. However, the mechanism of action for SENP1 in astrocytoma is not yet clear. Astrocytoma is the most frequent one among various neurogliomas, of which a subtype known as glioblastoma multiforme (GBM) is the most malignant brain glioma and seriously influences the life quality of the patients. In this study, the expression of SENP1 was detected in 28 cases of various grades of astrocytoma and 6 cases of normal human tissues. The results showed that the expression of SENP1 was positively correlated with the malignant grades. Besides, the NF-κB and Akt signaling pathways in GBM tissues were activated. Cytological experiments indicated that knock-down of endogenous SENP1 promoted cell apoptosis. Further research confirmed that downexpression of SENP1 could inhibit the phosphorylation of IκBα and Akt, and also the expression of its downstream regulation factors Bcl-xL and cyclinD1. These results delineate a key role for SENP1 in astrocytoma development, suggesting it may be a potential new therapeutic target inastrocytoma.

Introduction

SUMOylation is an important post-translational modification which is characterized by SUMO (small ubiquitin-related modifier) proteins covalently binding to intracellular target proteins. SUMO proteins are conjugated to > 200 proteins which display an important effect on protein stability, signal transduction, nucleoplasm transport, transcription regulation, DNA repair, and the regulation and control of cell cycle etc. (Hay, 2005, González-Santamaría et al., 2012). SUMOylation is a dynamic process which can be reversed by a family of SUMO-specific protease (SENP).

Recently, SENP1, a member of SENPs family, was shown to have a pro-oncogenic role in many types of cancer. SENP1 was observed to be overexpressed in lung cancer tissues, and the modulation of SENP1 expression was demonstrated to significantly affect the proliferation of lung cancer cells (Wang et al., 2013). SENP1 regulates cell migration and invasion in neuroblastoma and suppress SENP1 expression as promising candidates for novel treatment strategies of neuroblastoma (Xiang-Ming et al., 2015). SENP1 was also upregulated in pancreatic ductal adenocarcinoma (PDAC) tissues compared with adjacent normal tissues and regulates pancreatic cancer cell proliferation and invasion by targeting MMP-9 (Ma et al., 2014). Inhibition of SENP1 induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-κB signaling (Xu et al., 2015). In BV2 microglial cells, SENP1 inhibits the IH (Intermittent hypoxia)-induced apoptosis and nitric oxide production (Liu et al., 2015). SENP1 also positively regulated the expression of HIF-1α by deSUMOylation and weakened the sensitivity of hypoxic ovarian cancer cells to cisplatin (Ao et al., 2015). Although the up-regulation of SENP1 was observed in many types of human tumors, the concrete mechanism of SENP1 how regulates astrocytoma development is still unclear. Brain astrocytoma is the most frequent one among the various neurogliomas, the glioblastoma multiforme (GBM) out of which is the most malignant brain glioma subtype. Although there have been treatment methods at present, the prognosis is very poor and the life quality of patients was seriously influenced (Liu et al., 2007). In the process of genesis, development and malignant transformation, the expression of different signaling molecules all can accelerate or delay the progress of patients' condition. NF-κB pathway is considered as one of the treatment targets and in the activated state in GBM, blocking of which facilitated senescence of the differentiated cells (Nogueira et al., 2011). Also, the molecular mechanism underlying constitutive activation of AKT signaling plays essential roles in astrocytoma progression (Cai et al., 2015). To further elucidate the molecular mechanisms by which SENP1 regulates the growth and progression of astrocytoma, we detected the expression of SENP1 in different grade of astrocytoma and whether SENP1 can regulate U87MG and U251 cell apoptosis via NF-κB/Akt pathways.

Section snippets

Patients and tissue specimens

All the tissue samples were collected from the operative inpatients in the Department of Neurosurgery, the Second Hospital of Hebei Medical University, which was approved by Local and Medical Ethics Committee (Second Hospital of Hebei Medical Research Ethics Committee, Approval No. 2012003). We confirmed that the written informed consent was obtained from the next of kin in this study and the data of samples were analyzed anonymously. Our clinical investigation has been conducted according to

Analysis of SENP1 expression in normal brain and astrocytoma tissues

The expression of SENP1 was detected in 34 tissue samples from control people and patients with astrocytoma by RT-qPCR. The results demonstrated that the expression of SENP1 was significantly increased in the lower (II) and higher (III, IV) grades of astrocytomas in comparison with that in the normal brain tissues (p < 0.01) (Fig. 1A), which was consistent with the RT-PCR result (Fig. 1B). The results suggested that SENP1 had a positive correlation with the tumor malignant degree and might be

Discussion

It has been reported that over 200 intracellular target proteins can be SUMO-modified, including a great number of tumor genesis-related substrate proteins, such as AP-2, AR, c-Jun, c/EBP, c-Myb, CREB, Erm, Ets-1, GATA-2, HDACs, HSF1, IκBα, IRF-1, Pdx1, PTEN, p53, Sp3, STAT1, and TEL etc. (González-Santamaría et al., 2012, Bettermann et al., 2012), which display an important regulation effect on the stability of intracellular homeostasis. As an unique crucial deSUMOylation–specific proteinase,

Acknowledgments

This research was supported by Grants from Beijing Natured Scientific Foundation (No. 7164285) and the Major State Basic Research Development Program of China (973 Program) (No. 2011CB503803).

References (20)

K. Bettermann et al.
SUMOylation in carcinogenesis
Cancer Lett.
(2012)
J. Cai et al.
MicroRNA-542-3p suppresses tumor cell invasion via targeting AKT pathway in human astrocytoma.
J. Biol. Chem.
(2015)
J.M. Desterro et al.
SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation
Mol. Cell
(1998)
R.T. Hay
SUMO: a history of modification
Mol. Cell
(2005)
S. Liu et al.
SENP1 inhibits the IH-induced apoptosis and nitric oxide production in BV2 microglial cells
Biochem. Biophys. Res. Commun.
(2015)
B.D. Manning et al.
AKT/PKB signaling: navigating downstream
Cell
(2007)
J. Xu et al.
SENP1 inhibition induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-κB signaling
Biochem. Biophys. Res. Commun.
(2015)
Q. Ao et al.
SENP1 desensitizes hypoxic ovarian cancer cells to cisplatin by up-regulating HIF-1α
Sci Rep.
(2015)
J. González-Santamaría et al.
Regulation of the tumor suppressor PTEN by SUMO
Cell Death Dis.
(2012)
Y. Hu et al.
Platelet-derived growth factor BB mediates the glioma-induced migration of bone marrow-derived mesenchymal stem cells by promoting the expression of vascular cell adhesion molecule-1 through the PI3K, P38 MAPK and NF-κB pathways
Oncol. Rep.
(2013)

There are more references available in the full text version of this article.

Cited by (21)

Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis
2024, Redox Biology
Defects of human trophoblast cells may induce miscarriage (abnormal early embryo loss), which is generally regulated by lncRNAs. Ferroptosis is a newly identified iron-dependent programmed cell death. Hypoxia is an important and unavoidable feature in mammalian cells. However, whether hypoxia might induce trophoblast cell ferroptosis and then induce miscarriage, as well as regulated by a lncRNA, was completely unknown. In this work, we discovered at the first time that hypoxia could result in ferroptosis of human trophoblast cells and then induce miscarriage. We also identified a novel lncRNA (lnc-HZ06) that simultaneously regulated hypoxia (indicated by HIF1α protein), ferroptosis, and miscarriage. In mechanism, HIF1α-SUMO, instead of HIF1α itself, primarily acted as a transcription factor to promote the transcription of NCOA4 (ferroptosis indicator) in hypoxic trophoblast cells. Lnc-HZ06 promoted the SUMOylation of HIF1α by suppressing SENP1-mediated deSUMOylation. HIF1α-SUMO also acted as a transcription factor to promote lnc-HZ06 transcription. Thus, both lnc-HZ06 and HIF1α-SUMO formed a positive auto-regulatory feedback loop. This loop was up-regulated in hypoxic trophoblast cells, in RM villous tissues, and in placental tissues of hypoxia-treated mice, which further induced ferroptosis and miscarriage by up-regulating HIF1α-SUMO-mediated NCOA4 transcription. Furthermore, knockdown of either murine lnc-hz06 or Ncoa4 could efficiently suppress ferroptosis and alleviate miscarriage in hypoxic mouse model. Taken together, this study provided new insights in understanding the regulatory roles of lnc-HZ06/HIF1α-SUMO/NCOA4 axis among hypoxia, ferroptosis, and miscarriage, and also offered an effective approach for treatment against miscarriage.
SENP1-mediated SUMOylation of SIRT1 affects glioma development through the NF-κB pathway
2023, Experimental Cell Research
Gliomas are the most common primary brain tumors in adults. Although they exist in different malignant stages, most gliomas are clinically challenging because of their infiltrative growth patterns and inherent relapse tendency with increased malignancy. Epigenetic alterations have been suggested to be an important factor for glioma genesis. Using mRNA probe hybridization, we identified SUMO-specific protease 1 (SENP1) as the most significantly upregulated SUMOylation regulator in glioma. Moreover, SENP1 was overexpressed in gliomas and predicted poor prognoses. Depletion of SENP1 reduced glioma cell activity, cycle arrest, and increased apoptotic activity. Mechanistically, SENP1 inhibited the protein expression of sirtuin 1 (SIRT1) through de-SUMOylation, and SIRT1 inhibited the activity of nuclear factor kappaB (NF-κB) by deacetylation. Rescue experiments revealed that downregulation of SIRT1 reversed the inhibitory effect of sh-SENP1 on glioma cell malignant phenotype, while downregulation of NF-κB reversed the activating effect of sh-SIRT1 on glioma cell malignant phenotype. Thus, SENP1-mediated de-SUMOylation of SIRT1 might be therapeutically important in gliomas.
Emerging trends in post-translational modification: Shedding light on Glioblastoma multiforme
2023, Biochimica et Biophysica Acta - Reviews on Cancer
Recent multi-omics studies, including proteomics, transcriptomics, genomics, and metabolomics have revealed the critical role of post-translational modifications (PTMs) in the progression and pathogenesis of Glioblastoma multiforme (GBM). Further, PTMs alter the oncogenic signaling events and offer a novel avenue in GBM therapeutics research through PTM enzymes as potential biomarkers for drug targeting. In addition, PTMs are critical regulators of chromatin architecture, gene expression, and tumor microenvironment (TME), that play a crucial function in tumorigenesis. Moreover, the implementation of artificial intelligence and machine learning algorithms enhances GBM therapeutics research through the identification of novel PTM enzymes and residues. Herein, we briefly explain the mechanism of protein modifications in GBM etiology, and in altering the biologics of GBM cells through chromatin remodeling, modulation of the TME, and signaling pathways. In addition, we highlighted the importance of PTM enzymes as therapeutic biomarkers and the role of artificial intelligence and machine learning in protein PTM prediction.
A highly-stable layered Fe/Mn-based cathode with ultralow strain for advanced sodium-ion batteries
2021, Nano Energy
Citation Excerpt :
Meanwhile, as previously studied, the scavenging effect of Li dopant could also help to inhibit the TM cations dissolution and improve the interfacial stability [39]. Moreover, gas evolution, as another byproduct of the parasitic reactions (e.g., decomposition of the residual Na2CO3, electrolyte oxidation) on the cathode surface [57], was monitored by DEMS in the initial operation for the NFM and NLCFM cells. In Fig. 5e–f, the volume fraction of CO2 evolution is plotted as a function of time.
Sodium-ion batteries (SIBs) with iron- and manganese-based cathode electrodes have exhibited great promise in the grid-scale energy storage systems, on the basis of the satisfactory theoretical capacity, as well as huge abundance, low price and non-toxicity of raw materials. However, the inferior cycle life of cathode materials originating from their poor structural stability remains a formidable challenge towards practical applications. Here, an efficient strategy of improving the structure durability is demonstrated in iron- and manganese-based cathodes by dual heteroatom doping. The as-obtained P2-type Na_0.65Li_0.08Cu_0.08Fe_0.24Mn_0.6O₂ cathode delivers superior cyclability (88.2% capacity retention for 500 cycles at 2C), fabulous rate capability (76% capacity retention at 5C compared to 0.1C), and a useable reversible capacity of around 85 mAh g⁻¹ at 0.1C. Through in-depth characterizations, the underlying structure-property relationship is established, revealing that the complete solid-solution reaction during cycling ensures the ultralow volume variation (as small as 0.7%) and excellent electrochemical performance. These results highlight the significance of fabricating a stable host for the design and development of advanced SIBs with long life.
Emerging role of SENP1 in tumorigenesis and cancer therapy
2024, Frontiers in Pharmacology
Transcription factor YY1 mediates self-renewal of glioblastoma stem cells through regulation of the SENP1/METTL3/MYC axis
2023, Cancer Gene Therapy

View all citing articles on Scopus

View full text

Research paperInhibition of SUMO-specific protease 1 induces apoptosis of astroglioma cells by regulating NF-κB/Akt pathways

Highlights

Abstract

Introduction

Section snippets

Patients and tissue specimens

Analysis of SENP1 expression in normal brain and astrocytoma tissues

Discussion

Acknowledgments

Cancer Lett.

J. Biol. Chem.

Mol. Cell

Mol. Cell

Biochem. Biophys. Res. Commun.

Cell

Biochem. Biophys. Res. Commun.

SENP1 desensitizes hypoxic ovarian cancer cells to cisplatin by up-regulating HIF-1α

Sci Rep.

Regulation of the tumor suppressor PTEN by SUMO

Cell Death Dis.

Platelet-derived growth factor BB mediates the glioma-induced migration of bone marrow-derived mesenchymal stem cells by promoting the expression of vascular cell adhesion molecule-1 through the PI3K, P38 MAPK and NF-κB pathways

Oncol. Rep.

Research paper
Inhibition of SUMO-specific protease 1 induces apoptosis of astroglioma cells by regulating NF-κB/Akt pathways