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Published on: November 8, 2016
UBC12-mediated SREBP-1 neddylation worsens metastatic tumor prognosis
Mi Jeong Heo1, Sung Hyun Kang1, Yun Seok Kim1
1College of Pharmacy, Seoul National University, Seoul, South Korea.
Abstract:
Activation of sterol regulatory element-binding protein 1 (SREBP-1), a master lipogenic transcription factor, is associated with cancer metabolism and metabolic disorders. Neddylation, the process of adding NEDD8 to its substrate, contributes to diverse biological processes. Here, we identified SREBP-1 as a substrate for neddylation by UBC12 and explored its impact on tumor aggressiveness. In cell-based assays, SREBP-1 neddylation prolonged SREBP-1 stability with a decrease in ubiquitination. Consequently, NEDD8 overexpression facilitated proliferation, migration, and invasion of SK-Hep1 liver tumor cells. MLN4924 (an inhibitor of the NEDD8-activating enzyme-E1) treatment or UBC12 knockdown prevented SREBP-1 neddylation and tumor cell phenotype change. This effect was corroborated in an in vivo xenograft model. In human specimens, SREBP-1, UBC12, and NEDD8 were all upregulated in hepatocellular carcinoma (HCC) compared to nontumorous regions. Moreover, SREBP-1 levels positively correlated with UBC12. In GEO database analyses, SREBP-1 levels were greater in metastatic HCC samples accompanying UBC12 upregulation. In HCC analysis, tumoral SREBP-1 and UBC12 levels discriminated overall patient survival rates. Additionally, MLN4924 treatment destabilized SREBP-1 in MDA-MB-231 breast cancer cells and in the tumor cell xenograft. SREBP-1 and UBC12 were also highly expressed in human breast cancer tissues. Moreover, most breast cancers with lymph node metastasis displayed predominant SREBP-1 and UBC12 expressions, which compromised overall patient survival rates. In summary, SREBP-1 is neddylated by UBC12, which may contribute to HCC and breast cancer aggressiveness through SREBP-1 stabilization, and these events can be intervented by MLN4924 therapy. Our findings may also provide potential reliable prognostic markers for tumor metastasis.
Insights
Sterol regulatory element-binding protein 1 (SREBP-1) stabilization via neddylation by UBC12 promotes liver and breast cancer aggressiveness. Inhibiting this process with MLN4924 offers a potential therapeutic strategy and prognostic marker for tumor metastasis.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Sterol regulatory element-binding protein 1 (SREBP-1) is a key regulator of lipogenesis implicated in cancer metabolism.
- Neddylation, the conjugation of NEDD8 to proteins, influences various cellular processes.
- The role of SREBP-1 neddylation in cancer aggressiveness was previously unexplored.
Purpose of the Study:
- To identify SREBP-1 as a substrate for neddylation by UBC12.
- To investigate the impact of SREBP-1 neddylation on tumor aggressiveness in hepatocellular carcinoma (HCC) and breast cancer.
- To evaluate the therapeutic potential of inhibiting SREBP-1 neddylation.
Main Methods:
- Cell-based assays to assess SREBP-1 stability, ubiquitination, and proliferation, migration, and invasion.
- In vivo xenograft models to validate findings.
- Analysis of human HCC and breast cancer specimens and GEO database for SREBP-1, UBC12, and NEDD8 expression.
- Treatment with MLN4924 (NEDD8-activating enzyme inhibitor) and UBC12 knockdown.
Main Results:
- SREBP-1 was identified as a substrate for neddylation by UBC12, leading to increased SREBP-1 stability and decreased ubiquitination.
- NEDD8 overexpression enhanced proliferation, migration, and invasion in liver tumor cells.
- MLN4924 treatment or UBC12 knockdown inhibited SREBP-1 neddylation and reversed tumor cell phenotype changes.
- Upregulation of SREBP-1, UBC12, and NEDD8 was observed in HCC and breast cancer tissues, correlating with tumor aggressiveness and poorer patient survival.
- MLN4924 treatment destabilized SREBP-1 in breast cancer cells and xenografts.
Conclusions:
- SREBP-1 is neddylated by UBC12, contributing to HCC and breast cancer aggressiveness via SREBP-1 stabilization.
- Inhibition of SREBP-1 neddylation by MLN4924 presents a potential therapeutic strategy.
- SREBP-1 and UBC12 may serve as prognostic markers for tumor metastasis and patient survival.
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