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• Research Paper Volume 12, Issue 2 pp 1563-1576

  SENP1 is a crucial promotor for hepatocellular carcinoma through deSUMOylation of UBE2T

  Relevance score: 8.081901

  Yifeng Tao, Ruidong Li, Conghuan Shen, Jianhua Li, Quanbao Zhang, Zhenyu Ma, Feifei Wang, Zhengxin Wang

  Keywords: hepatocellular carcinoma, SENP1, deSUMOylation, UBE2T, Akt

  Published in Aging on January 22, 2020

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  The cooperative roles of SENP1 and UBE2T in development and progression of hepatocellular carcinoma (HCC) are still unknown. The expression levels of SENP1 and UBE2T were evaluated in clinical specimens and HCC cells. The relationship between clinicopathological features and SENP1 were analyzed. We constructed the HepG2-SENP1 knockout cell model and explored the functions of SENP1 and UBE2T in HCC development. UBE2T was confirmed as a novel deSUMOylation target of SENP1. Upregulation of SENP1 and UBE2T were observed in HCC tissues and most hepatoma cell lines, and their expression levels were proved to be positively related. Knockout of SENP1 resulted in impaired growth, migration and invasion, and enhanced apoptosis in vitro, as well as inhibition of tumor growth in vivo. Furthermore, we demonstrated that SENP1 could directly deSUMOylate UBE2T thereby increasing its expression and activating Akt pathway. Functional studies showed that UBE2T overexpression or K8R mutation promoted cell growth, migration and invasion. In conclusion, our study demonstrated that SENP1 and UBE2T were positively related and functioned as tumor promoters. The carcinogenesis of SENP1 is mediated by deSUMOylation of UBE2T and the UBE2T/Akt pathway. Notably, UBE2T was identified as a novel deSUMOylation target of SENP1 in this study for the first time.

  

  SENP1 is overexpressed in HCC tissues. (A) The protein levels of SENP1 in adjacent normal tissues and tumor tissues were examined by Western blot. (B) The average relative protein levels of SENP1 in adjacent normal tissues and tumor tissues obtained from gray analysis of Western blot results. (C) The expression of SENP1 in adjacent normal tissues and tumor tissues was determined by immunohistochemical staining. (D) Kaplan-Meier’s analysis of the correlation between SENP1 levels and overall survival in HCC patients. (E, F) SENP1 expression in TCGA RNAseq database. (G) The association between SENP1 expression and survival rate in TCGA database. The representative images were selected from at least three independent experiments.

  
  
  

  

  SENP1 knockout inhibits cell proliferation and motion, and induces cell cycle dysregulation. (A) The protein levels of SENP1 in normal hepatic cells and nine HCC cell lines were measured using Western blot. (B) SENP1 knockout was confirmed by Western blot. (C) The effect of SENP1 knockout on HepG2 cell proliferation was determined using cell count assay. (D) The effects of SENP1 knockout on HepG2 cell colony formation were examined using colony formation assay. (E) The effects of SENP1 knockout on HepG2 cell cycle distribution were analyzed by using flow cytometry. (F) The effects of SENP1 knockout on P53, P21 and CyclinD1 mRNA levels were measured using RT-PCR. (G) The effects of SENP1 knockout on HepG2 cell migration were determined using wound healing assay. (H) The effects of SENP1 knockout on HepG2 cell invasion were examined using Transwell assay. The representative images were selected from at least three independent experiments. *P<0.05, **P<0.01, ***P<0.001.

  
  
  

  

  UBE2T is overexpressed in HCC tissues and cell lines. (A) SENP1-related interaction network was constructed based on String database. (B) Correlation analysis of SENP1 and UBE2T expression was performed based on gene expression profiling data of TCGA. (C) The protein levels of UBE2T in adjacent normal tissues and tumor tissues were examined by western blot. (D) The average relative protein levels of UBE2T in adjacent normal tissues and tumor tissues obtained from gray analysis of Western blot results. (E) The expression of UBE2T in adjacent normal tissues and tumor tissues was determined by immunohistochemical staining. (F, G) UBE2T expression in TCGA RNAseq database. (H, I) The association between UBE2T expression or SENP1+UBE2T expression and survival rate in TCGA database or KM plotter dataset. (J) Expression of SENP1 and UBE2T were positively related in HCC clinical samples. The data were analyzed with Pearson correlation by GraphPad prism 6.0. The representative images were selected from at least three independent experiments.

  
  
  

  

  SENP1 promotes UBE2T signaling pathway. (A, B) SENP1 knockout inhibited the mRNA level of UBE2T, which was reversed by UBE2T overexpression. (C, D) SENP1 knockout inhibited the activation of Akt, which was reversed by UBE2T overexpression. (E) UBE2T overexpression weakened the effect of SENP1 knockout in P53, P21 and CyclinD1 levels. The representative images were selected from at least three independent experiments. *P<0.05, **P<0.01, ***P<0.001.

  
  
  

  

  SENP1 deSUMOylates UBE2T. (A) Comparative analysis of UBE2T in different species. (B) The effect of SENP1 knockout on SUMO-UBE2T complex was determined using co-Immunoprecipitation. (C) The effect of UBE2T-overexpression and UBE2T-K8R mutation co-expressed with SENP1 knockout on SUMO-UBE2T complex was determined using co-Immunoprecipitation.

  
  
  

  

  Effect of UBE2T overexpression or K8R mutation on cell function and its downstream signaling pathway. (A) The effects of UBE2T overexpression and K8R mutation on HepG2 cell proliferation were determined using CCK-8 assay. (B) The effects of UBE2T overexpression and K8R mutation on HepG2 cell colony formation were examined using colony formation assay. (C) The effects of UBE2T overexpression and K8R mutation on HepG2 cell migration were determined using wound healing assay. (D) The effects of UBE2T overexpression and K8R mutation on HepG2 cell invasion were examined using Transwell assay. (E) The effects of UBE2T overexpression and K8R mutation on p53 and p21 mRNA levels. The representative images were selected from at least three independent experiments. *P<0.05, **P<0.01, ***P<0.001.

  
  
  

  

  SENP1 knockout attenuates the tumorigenic potential in vivo. (A) Tumor growth of mice injected with HepG2-control or HepG2-SENP1 KO. (B) Representative tumors of negative control groups and SENP1 KO groups. (C) The average final tumor size and weight in negative control groups and SENP1-KO groups. (D) UBE2T expression in xenograft tumor tissues by immunohistochemical staining. (E) UBE2T, p-Akt and Akt protein levels in xenograft tumor tissues by Western blot. (F) P53 and P21 mRNA levels in xenograft tumor tissues by RT-PCR. (G) The schematic diagram briefly demonstrating the molecular mechanism of SENP1 mediated promotion of HCC. The representative images were selected from at least three independent experiments. *P<0.05, **P<0.01, ***P<0.001.