Small ubiquitin-related modifier 1 is involved in hepatocellular carcinoma progression via mediating p65 nuclear translocation

Abstract

Small ubiquitin-related modifier (SUMO) proteins participate in a post-translational modification called SUMOylation and regulate a variety of intracellular processes, such as targeting proteins for nuclear import. The nuclear transport of p65 results in the activation of NF-κB, and p65 contains several SUMO interacting motifs (SIMs). However, the relationship between p65 and SUMO1 in hepatocellular carcinoma (HCC) remains unclear. In this study, we demonstrated the potential roles of SUMO1 in HCC via the regulation of p65 subcellular localization. We found that either SUMO1- or p65-positive immunoreactivity was remarkably increased in the nuclei of tumor tissues in HCC patients compared with non-tumor tissues, and further analysis suggested a correlation between SUMO1- and nuclear p65-positive immunoreactivities (R = 0.851, P = 0.002). We also verified the interaction between p65 and SUMO1 in HCC by co-immunoprecipitation. TNF-α and hypoxia increased SUMO1 protein levels and enhanced SUMO1-modified p65 SUMOylation. Moreover, the knockdown of SUMO1 decreased p65 nuclear translocation and inhibited NF-κB transcriptional activity. Further the results of this study revealed that the knockdown of SUMO1 suppressed the proliferation and migration of hepatoma cells. These results suggest that SUMO1 contributes to HCC progression by promoting p65 nuclear translocation and regulating NF-κB activity.

Mesencephalic Astrocyte‐Derived Neurotrophic Factor Inhibits Liver Cancer Through Small Ubiquitin‐Related Modifier (SUMO)ylation‐Related Suppression of NF‐κB/Snail Signaling Pathway and Epithelial‐Mesenchymal Transition

“…Our previous data showed that SUMO1 overexpression up‐regulated the nuclear transport of p65, and SUMO1 knockdown down‐regulated p65 nuclear translocation in hepatoma cells . However, our data also showed that SUMO1, either by overexpression or knockdown, led to inhibition of the NF‐κB transcriptional activity . The underlying mechanism is unclear.…”

“…The underlying mechanism is unclear. p65, as a transcriptional factor, can be SUMOylated by SUMO1 and SUMO2/3 proteins in hepatoma cells . Interestingly, we found that SUMO1 knockdown inhibited the interaction of MANF and p65 in the nucleus.…”

“…It was thought that low‐level transcription factor SUMOylation can lead to repression of transcriptional activity . Our previous data showed that p65, as a transcription factor, can be SUMOylated by SUMO1 and SUMO2/3 . We searched for the SUMO‐interaction/binding motif (SIM/SBM) of p65 by using SUMOsp2.0 software.…”

“…by SUMO1 and SUMO2/3. (23,24) We searched for the SUMO-interaction/binding motif (SIM/ SBM) of p65 by using SUMOsp2.0 software. The result indicates that p65 is a protein containing SIM/SBM at Lys37, Lys122, Lys123, and Lys221 (Fig.…”

SUMOylation and phosphorylation cross-talk in hepatocellular carcinoma

“…In details, p65 SUMOylation could be mediated by SUMO proteins that recruit an inhibitor of p65 in nucleus may be via SUMO-2/3 that has been described to inhibit nuclear import of p65 (58). Subsequentially, SUMO-2 or SUMO-3 induced the cytoplasmic level of p65 and may suppress its transcriptional activity (57,59). …”