TRIM21–SERPINB5 aids GMPS repression to protect nasopharyngeal carcinoma cells from radiation-induced apoptosis

Abstract

Background: The main strategy against nasopharyngeal carcinoma (NPC) is radiotherapy. However, radioresistance mediated recurrence is a leading clinical bottleneck in NPC. Revealing the mechanism of NPC radioresistance will help improve the therapeutic effect. Methods: In this study, the role of TRIM21 (tripartite motif-containing 21) in NPC receiving ionizing radiation was firstly examined both in vivo and in vitro. Mass spectrometry analysis was performed to identify the downstream targets of TRIM21. NPC cells with TRIM21 or SERPINB5 (serpin family B member 5) overexpression or knockout were used to determine the epistatic relationship among SERPINB5, GMPS (guanine monophosphate synthase) and TRIM21. Flow cytometry, co-immunoprecipitation, western blot and immunofluorescence were employed to strengthen the results. Finally, immunohistochemistry using 4 radiosensitive and 8 radioresistent NPC patient samples was perform to examine the association between SERPINB5 or GMPS expression and patient radiosensitivity. Results: As an E3 ligase, TRIM21 was highly expressed in NPC. After ionizing radiation, TRIM21 repressed TP53 expression by mediating GMPS ubiquitination and degradation. Overexpression of TRIM21 protected NPC cells from radiation mediated cell apoptosis in vitro and in vivo. Further analysis revealed that TRIM21 mediated GMPS repression was dependent on SERPINB5, and SERPINB5 served as an adaptor which prevented GMPS from entering into the nucleus and introduced TRIM21 for GMPS ubiquitination. Moreover, the in vitro and in vivo results validated the finding that SERPINB5 promoted NPC cell radioresistance, and the radioresistant patients had higher SERPINB5 expression. Conclusions: Overall, our data showed that TRIM21-SERPINB5-mediated GMPS degradation facilitated TP53 repression, which promoted the radioresistance of NPC cells. This novel working model related to TP53 suppression provided new insight into NPC radioresistence clinically.

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“…With the current treatment, the 5-year survival rate of ESCC is still low worldwide (27,28), especially in developing countries. One major reason is lacking recurrence prevention drugs (29,30). According to retrospective studies, many drugs marketed for other diseases have shown an anti-tumor effect, which make them probably can be used for cancer recurrence prevention (31)(32)(33).…”

Targeting the signaling in Epstein–Barr virus-associated diseases: mechanism, regulation, and clinical study

“… 186 Transcription factor p53 is a critical mediator that is directly phosphorylated and stabilized by DNA damage signaling kinases, which triggers the apoptotic program. 187 Zhang et al 188 found that RING-finger domain-containing ubiquitin E3 ligase tripartite motif–containing 21 (TRIM21) repressed p53 expression by mediating guanine monophosphate synthase (GMPS) ubiquitination and degradation. TRIM21 protects NPC cells from radiation-induced apoptosis by manipulating the GMPS–p53 cascade.…”

“…TRIM21 protects NPC cells from radiation-induced apoptosis by manipulating the GMPS–p53 cascade. 188 In addition, TRIM21 is also responsible for the polyubiquitination of prohibitin 1 (PHB1), a pleiotropic protein that functions as a tumor suppressor. Ubiquitination and degradation of PHB1 leads to transcriptional activation of NF-κB and STAT3.…”

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“…GMPS is a classic biosynthetic enzyme that promotes cell proliferation and DNA replication, most of the existing research on GMPS has been performed in bacteria and insects, it has been reported that GMPS is involved in chromatin and gene regulation ( 8 , 12 , 22 ). A previous study revealed that GMPS metabolism serves an important role in controlling the invasion and tumorigenicity of human melanoma cells.…”

“…GMPS is upregulated in numerous malignant tumors, such as lung squamous cell carcinoma, ovarian serous cystadenocarcinoma and head and neck squamous cell carcinoma ( 11 - 13 ). A previous study revealed that GMPS participates in radiotherapy resistance and plays a role in inducing cell apoptosis of nasopharyngeal carcinoma ( 12 ). It has been reported that the expression of GMPS strongly affects the invasive capacity of melanoma cells and ultimately tumor growth, and angustmycin A, a nucleoside-analog inhibitor of GMPS produced by Streptomyces hygroscopicus efficiently suppresses melanoma cell invasion in vitro and tumorigenicity in immunocompromised mice ( 14 ).…”