Objective SUMO-specific protease 3(SENP3),a member of the SUMO-specific protease family,reverses the SUMOylation of SUMO-2/3 conjugates.Dysregulation of SENP3 has been proven to be involved in the development of vario...Objective SUMO-specific protease 3(SENP3),a member of the SUMO-specific protease family,reverses the SUMOylation of SUMO-2/3 conjugates.Dysregulation of SENP3 has been proven to be involved in the development of various tumors.However,its role in mantle cell lymphoma(MCL),a highly aggressive lymphoma,remains unclear.This study was aimed to elucidate the effect of SENP3 in MCL.Methods The expression of SENP3 in MCL cells and tissue samples was detected by RT-qPCR,Western blotting or immunohistochemistry.MCL cells with stable SENP3 knockdown were constructed using short hairpin RNAs.Cell proliferation was assessed by CCK-8 assay,and cell apoptosis was determined by flow cytometry.mRNA sequencing(mRNA-seq)was used to investigate the underlying mechanism of SENP3 knockdown on MCL development.A xenograft nude mouse model was established to evaluate the effect of SENP3 on MCL growth in vivo.Results SENP3 was upregulated in MCL patient samples and cells.Knockdown of SENP3 in MCL cells inhibited cell proliferation and promoted cell apoptosis.Meanwhile,the canonical Wnt signaling pathway and the expression of Wnt10a were suppressed after SENP3 knockdown.Furthermore,the growth of MCL cells in vivo was significantly inhibited after SENP3 knockdown in a xenograft nude mouse model.Conclusion SENP3 participants in the development of MCL and may serve as a therapeutic target for MCL.展开更多
细胞在受到内源、外源的氧化物刺激时均能启动应答机制,改变蛋白质的量、定位和活性来抵抗应激。作者前期的研究发现,SUMO特异蛋白酶SENP3(Sentrin/SUMO specific protease3)可以感受一定程度的氧化应激而发生量的累积,从而影响一系列...细胞在受到内源、外源的氧化物刺激时均能启动应答机制,改变蛋白质的量、定位和活性来抵抗应激。作者前期的研究发现,SUMO特异蛋白酶SENP3(Sentrin/SUMO specific protease3)可以感受一定程度的氧化应激而发生量的累积,从而影响一系列转录因子的SUMO化修饰状态和特异基因表达,发挥应答应激的功能,但在不同程度氧化应激时SENP3是否有不同的感受和应答机制并不清楚。该研究应用不同剂量H2O2模拟不同程度氧化应激,探讨SENP3的量、定位改变和对抗氧化蛋白表达的影响。结果显示,轻度氧化应激即可造成SENP3量的增加,但无H2O2剂量相关关系,而不同程度氧化应激均可引起SENP3从核仁向核质的移位,且随H2O2剂量增加而增加。在氧化应激引起的过氧化物氧还蛋白4(peroxiredoxin 4,Prx4)、超氧化物歧化酶1(superoxide dismutase1,SOD1)及过氧化氢酶(catalase,CAT)表达上调中,SENP3介导了这种表达改变,且有H2O2剂量相关性。该研究一方面发现了SENP3感受不同程度氧化应激的两种机制,另一方面也发现了SENP3介导抗氧化应答的功能,提示SENP3在细胞精细的应激应答机制中扮演了重要角色,具有一定的生理和病理意义。展开更多
SUMOylation is recently found to function as a targeting signal for the degradation of substrates through the ubiquitin-proteasome system. RNF4 is the most studied human SUMO-targeted ubiquitin E3 ligase. However, the...SUMOylation is recently found to function as a targeting signal for the degradation of substrates through the ubiquitin-proteasome system. RNF4 is the most studied human SUMO-targeted ubiquitin E3 ligase. However, the relationship between SUMO proteases, SENPs, and RNF4 remains obscure. There are limited examples of the SENP regulation of SUMO2/3-targeted proteolysis mediated by RNF4. The present study investigated the role of SENP3 in the global protein turnover related to SUMO2/3-targeted ubiquitination and focused in particular on the SENP3 regulation of the stability of Spl. Our data demonstrated that SENP3 impaired the global ubiquitination profile and promoted the accumulation of many proteins. Spl, a cancer-associated transcription factor, was among these proteins. SENP3 increased the level of Spl protein via antagonizing the SUMO2/3-targeted ubiquitination and the consequent proteasome-dependent degradation that was mediated by RNF4. De-conjugation of SUMO2/3 by SENP3 attenuated the interaction of Spl with RNF4. In gastric cancer cell lines and specimens derived from patients and nude mice, the level of Spl was generally increased in parallel to the level of SENP3. These results provided a new explanation for the enrichment of the Spl protein in various cancers, and revealed a regulation of SUMO2/3 conjugated proteins whose levels may be tightly con- trolled by SENP3 and RNF4.展开更多
基金supported by the Chongqing Natural Science Foundation(No.2023NSCQ-MSX3161 and No.cstc2020jcyj-msxmX1058)the National Natural Science Foundation of China(No.81800172).
文摘Objective SUMO-specific protease 3(SENP3),a member of the SUMO-specific protease family,reverses the SUMOylation of SUMO-2/3 conjugates.Dysregulation of SENP3 has been proven to be involved in the development of various tumors.However,its role in mantle cell lymphoma(MCL),a highly aggressive lymphoma,remains unclear.This study was aimed to elucidate the effect of SENP3 in MCL.Methods The expression of SENP3 in MCL cells and tissue samples was detected by RT-qPCR,Western blotting or immunohistochemistry.MCL cells with stable SENP3 knockdown were constructed using short hairpin RNAs.Cell proliferation was assessed by CCK-8 assay,and cell apoptosis was determined by flow cytometry.mRNA sequencing(mRNA-seq)was used to investigate the underlying mechanism of SENP3 knockdown on MCL development.A xenograft nude mouse model was established to evaluate the effect of SENP3 on MCL growth in vivo.Results SENP3 was upregulated in MCL patient samples and cells.Knockdown of SENP3 in MCL cells inhibited cell proliferation and promoted cell apoptosis.Meanwhile,the canonical Wnt signaling pathway and the expression of Wnt10a were suppressed after SENP3 knockdown.Furthermore,the growth of MCL cells in vivo was significantly inhibited after SENP3 knockdown in a xenograft nude mouse model.Conclusion SENP3 participants in the development of MCL and may serve as a therapeutic target for MCL.
文摘细胞在受到内源、外源的氧化物刺激时均能启动应答机制,改变蛋白质的量、定位和活性来抵抗应激。作者前期的研究发现,SUMO特异蛋白酶SENP3(Sentrin/SUMO specific protease3)可以感受一定程度的氧化应激而发生量的累积,从而影响一系列转录因子的SUMO化修饰状态和特异基因表达,发挥应答应激的功能,但在不同程度氧化应激时SENP3是否有不同的感受和应答机制并不清楚。该研究应用不同剂量H2O2模拟不同程度氧化应激,探讨SENP3的量、定位改变和对抗氧化蛋白表达的影响。结果显示,轻度氧化应激即可造成SENP3量的增加,但无H2O2剂量相关关系,而不同程度氧化应激均可引起SENP3从核仁向核质的移位,且随H2O2剂量增加而增加。在氧化应激引起的过氧化物氧还蛋白4(peroxiredoxin 4,Prx4)、超氧化物歧化酶1(superoxide dismutase1,SOD1)及过氧化氢酶(catalase,CAT)表达上调中,SENP3介导了这种表达改变,且有H2O2剂量相关性。该研究一方面发现了SENP3感受不同程度氧化应激的两种机制,另一方面也发现了SENP3介导抗氧化应答的功能,提示SENP3在细胞精细的应激应答机制中扮演了重要角色,具有一定的生理和病理意义。
文摘SUMOylation is recently found to function as a targeting signal for the degradation of substrates through the ubiquitin-proteasome system. RNF4 is the most studied human SUMO-targeted ubiquitin E3 ligase. However, the relationship between SUMO proteases, SENPs, and RNF4 remains obscure. There are limited examples of the SENP regulation of SUMO2/3-targeted proteolysis mediated by RNF4. The present study investigated the role of SENP3 in the global protein turnover related to SUMO2/3-targeted ubiquitination and focused in particular on the SENP3 regulation of the stability of Spl. Our data demonstrated that SENP3 impaired the global ubiquitination profile and promoted the accumulation of many proteins. Spl, a cancer-associated transcription factor, was among these proteins. SENP3 increased the level of Spl protein via antagonizing the SUMO2/3-targeted ubiquitination and the consequent proteasome-dependent degradation that was mediated by RNF4. De-conjugation of SUMO2/3 by SENP3 attenuated the interaction of Spl with RNF4. In gastric cancer cell lines and specimens derived from patients and nude mice, the level of Spl was generally increased in parallel to the level of SENP3. These results provided a new explanation for the enrichment of the Spl protein in various cancers, and revealed a regulation of SUMO2/3 conjugated proteins whose levels may be tightly con- trolled by SENP3 and RNF4.
