Small ubiquitin-like modifier (SUMO) is a highly conserved post-translational modification protein, mainly found in eukaryotes. They are widely expressed in different tissues, including the liver. As an essential post-translational modification, SUMOylation is involved in many necessary regulations in cells. It plays a vital role in DNA repair, transcription regulation, protein stability and cell cycle progression. Increasing shreds of evidence show that SUMOylation is closely related to Hepatocellular carcinoma (HCC).
Actions | Models | Regulation/ Pathway |
Effects | Reference | |
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HCC carcinogenesis | In Vitro, MHCC97H, MHCC97L, MHCC-LM and QGY7703Hep3B, HepG2, Huh7, SMMC-7721, BEL-7402, BEL-7404. In vivo, male BALB/c nude mice (5 weeks old) |
SIRT1-FTO | SUMO ligase E3 RANBP2 promotes SIRT1-related FTP down-regulation | [53] 2020 | [27] 2020 |
in vitro, HepG2 | IQGAP2 | SUMOylation inhibits AKT phosphorylation through cross-talk, thereby inhibiting the expression of HBV genes. | [54] 2019 | [28] 2019 |
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In vitro. HEK293T, SMMC-7721 and HepG2 cells | ROS&PHGDH | SUMOylised NRF2 can upregulate the synthesis of serine in HCC. | [50] 2019 | [29] 2019 |
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In vitro, SMMC-7721, HepG2 and SMMC-7721-shShp2 | ERK | Shp2 SUMOylation upregulates the activation of ERK | [55] 2015 | [30] 2015 |
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In vitro, HepG2, HepG2X, Hep3B, SK-Hep1, HuH7 and Hep3BX cells | CPAP | TNF-α can upregulate SUMO-1 mediated CPAP SUMOylation, which is very important for NF-κB co-activator activity. | [56] 2013 | [31] 2013 |
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In Vitro, MHCC97H, HepG2, HEP3B and SMMC-7721. In vivo, Four-week-old female BALB/c nude mice |
UBC9, SUMOylated Mettl3 and Snail | SUMOylate Mettls can regulate the homeostasis of Snail mRNA through m6A methyltransferase activity-dependent manner. And then regulate the development of HCC. | [57] 2020 | [32] 2020 |
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HCC proliferation and survival | in vitro, hepg2 and smmc7721 In clinical, HCC patient |
NF-κB | SUMO2/3 and P65 are co-expressed and co-localised in HCC. | [58] 2015 | [33] 2015 |
In vitro, MHCC97L &SMMC-7721 cells | Cbx4 | CBx4 can control HIF-1α, thereby upregulating the angiogenesis of HCC. SUMO’s E3 ligase controls this activity. | [49] 2014 | [34] 2014 |
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In vitro, HepG2 cells | WWOX | WWOX can help SENP2 stabilisation of β-catenin. | [59] 2014 | [35] 2014 |
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In-clinic, Patients HCC cells | HIF-1/2α | SENP1 can de-SUMOylation HIF-1α and increase its stability. | [60] 2016 | [36] 2016 |
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In vitro, HepG2 cells | NF-κB | SUMO1 and P65 are co-expressed and co-localised. Up-regulation of SUMO1 can upregulate NF-κB activity and promote the progression of HCC. | [61] 2016 | [37] 2016 |
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In vivo, Male BALB/c nude mice | ATR | SUMOylation of ART can upregulate the proliferation of HCC cells. | [62] 2016 | [38] 2016 |
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In vitro, human LCSC In-clinic, 60 HCC patients. |
TRF2 | HULC can enhance phosphorylation, thereby suppressing SUMOylation. | [63] 2016 | [39] 2016 |
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in vitro, HEK293T, L02 normal human hepatic cells, HepG2 human hepatocellular | Lats | The SUMOylation of Lats1 can upregulate Hippo signalling. | [64] 2017 | [40] 2017 |
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in vitro, Huh-7, Hep G2 and PLC/PRF/5 and MLP-29 | lkb1 | SUMO2-mediated SUMOylation of LKB1 can affect its location in cells and promote carcinogenesis. | [65] 2020 | [41] 2020 |
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HCC migration, invasion and metastasis | In vitro, PHHs, MHCC-97H and HCCLM3. In-clinic, human HCC patient |
P53 hnRNP SUMOlyation | The SUMOylation of hnRNP k can activate the P53 signal, thereby inhibiting tumour progression. | [66] 2020 | [42] 2020 |
In vitro, Huh-7 and HepG-2In-clinic, Cancer tissues and Paracancerous tissues for 38 patients. | NF-κB | The SUMOylation of NEMO can upregulate the activity of NF-κB, thereby promoting the invasion of HCC. | [24] 2020 |
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In Vivo, MANF-KO [knockout] mice In-Clinic, Human HCC cells |
NF-κB | SUMO1 co-localises with P65 and MANF. Thereby promoting the interaction between P65 and MANF. | [25] 2020 |
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in vitro, Huh7, SK-Hep1, Hep3B, Hep3BX, HepG2 and HepG2X cells | HBx | CPAP can upregulate the SUMOylation of HBx. | [67] 2019 | [43] 2019 |
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in vivo, Hnf1a-null mice | mrR192/194 | SUMO2 is miR194′s target. | [68] 2017 | [44] 2017 |
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In-clinic, HCC patient | hsp27 | SUMO2/3 upregulated the HSP27 protein level. | [69] 2017 | [45] 2017 |
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In vivo, HBx mice | IGF-II | SUMOylation of E-cadherin causes it to degrade. | [70] 2015 | [46] 2015 |
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In vitro, MHCC97L cells | Cbx4 | Cbx4 can upregulate the SUMOylation of HIF-1α and shape the hypoxic microenvironment. | [49] 2014 | [34] 2014 |
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In vitro, HepG2, Hep3B and MHCC97H and standard liver cancer cell lines THLE-2 and LO2 | Exportin-5 (XPO5) | SUMOylated XPO5 down-regulating the nucleo-cytoplasm transportation of pre-miR-3184 | [71] 2020 | [47] 2020 |
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HCC tumour microenvironment | In Vitro, HCC cell line Hep3B | HIF-1α and Oct4 | deSUMOylation of HIF-1α and Oct4 reduced their accumulation in the nucleus, thereby inhibiting tumour angiogenesis and stemness maintenance. | [72] 2020 | [48] 2020 |
In-clinic, human blood samples | PKM2 | SUMOylation of PKM2 induced its plasma membrane targeting and subsequent exosomal excretion via interactions with ARRDC1. | [73] 2020 | [49] 2020 |
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in vitro, Hep3B cells In-clinic, 10 HCC patients |
SHh | SUMOylation of GLI protein can upregulate its hypoxia-dependent activation. | [74] 2019 | [50] 2019 |
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In-clinic, HCC patients. | NF-κB | Sorafenib treatment treats HCC by inhibiting the SUMOylation of p65. | [75] 2018 | [51] 2018 |
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In vitro, HepG2 and SMMC-7721 | UBC9 | UBC9 E2 conjugating enzyme is necessary for the SUMOylation process. | [69] 2017 | [45] 2017 |
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In vitro, HepG2 in-clinic, HCC patient |
not mentioned | not mentioned | [76] 2015 | [52] 2015 |