| Modification of proteins by small ubiquitin-like modifiers(SUMO) is a dynamic and reversible process. SUMO can be removed from its substrates by proteases that belong to the sentrin-specific proteases(SENPs) family. The previous work of our lab has showed that, SENP3, the only redox-sensitive SUMO2/3-specific protease in SENP family, accumulates under cellular redox stress. It can promote the growth and proliferation of cancer cells, as well as angiogenesis by de-SUMOylating P300 or PML, which have been the earlist report about that SENP3 facilitates cancer development. Because of high reactive oxygen in cancers, the content of SENP3 keeps in high level in gastric cancer. However, whether SENP3 participates in the progress of gastric cancer and which signal pathway is involved are unclear.On the basis of the known knowledge about SENP3, to explore the new targets of SENP3 and the regulatory mechanism, this study is divided into two parts to reveal how SENP3 affects the progress of gastric cancer by regulating the targets.In the first part of the thesis, we demonstrated that SENP3 can regulate the ubiquitin profile of global proteins and the Sp1 stability by antagonizing the SUMO-targeted ubiquitination pathway. This study first shows the function of SENP3 regulating the ubiquitin profile of global proteins. The basic transcription factor Sp1 accumulates in pancreatic cancer, gastric cancer, breast cancer and is related to tumor metastasis and poor prognosis. This is the first study to show that SENP3 de-SUMOylates Sp1 to inhibit SUMO-targeted ubiquitination pathway. The mechanism of SENP3 regulating Sp1 stability explains why Sp1 stays high level in these cancers and how SENP3 promotes the progress of gastric cancer. Even more important, this research proves for the first time that SENP3 antagonises the SUMO-targeted ubiquitin E3 ligase RNF4, which provides a new perspective for SENPs regulating the SUMO-targeted ubiquitination pathway.The previous results of our lab indicated that SENP3 can induce EMT by upregulating the expression of FOXC2. The second part of the present work aimed to look for which transcription factors SENP3 regulate to promote the FOXC2 expression whose increase can induce EMT. By analyzing the promoter region of FOXC2, we investigated preliminarily whether Sp1 and AP2α are the transcription factors of FOXC2 using dual luciferase report gene assay. The results displayed that Sp1 is the transcription factor of FOXC2. AP2α can be SUMOylated by SUMO3 and de-SUMOylated by SENP3.This study provides new clues about how SENP3 induces EMT and is the first investigation on the transcription factor of FOXC2. |
