Inactivation of SAG/RBX2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis
Abstract:
Cullin-RING ligases (CRLs) are a family of E3 ubiquitin ligase complexes that rely on either RING-box 1 (RBX1) or sensitive to apoptosis gene (SAG), also known as RBX2, for activity. RBX1 and SAG are both overexpressed in human lung cancer; however, their contribution to patient survival and lung tumorigenesis is unknown. Here, we report that overexpression of SAG, but not RBX1, correlates with poor patient prognosis and more advanced disease. We found that SAG is overexpressed in murine KrasG12D-driven lung tumors and that Sag deletion suppressed lung tumorigenesis and extended murine life span. Using cultured lung cancer cells, we showed that SAG knockdown suppressed growth and survival, inactivated both NF-κB and mTOR pathways, and resulted in accumulation of tumor suppressor substrates, including p21, p27, NOXA, and BIM. Importantly, growth suppression by SAG knockdown was partially rescued by simultaneous knockdown of p21 or the mTOR inhibitor DEPTOR. Treatment with MLN4924, a small molecule inhibitor of CRL E3s, also inhibited the formation of KrasG12D-induced lung tumors through a similar mechanism involving inactivation of NF-κB and mTOR and accumulation of tumor suppressor substrates. Together, our results demonstrate that Sag is a Kras-cooperating oncogene that promotes lung tumorigenesis and suggest that targeting SAG-CRL E3 ligases may be an effective therapeutic approach for Kras-driven lung cancers.
Insights
Sensitive to apoptosis gene (SAG) overexpression, not RBX1, correlates with poor lung cancer prognosis. Sag deletion suppressed tumor growth and extended lifespan, suggesting SAG-CRL E3 ligases as a therapeutic target for Kras-driven lung cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Cullin-RING ligases (CRLs) are crucial E3 ubiquitin ligase complexes.
- RBX1 and SAG (RBX2) are key components of CRLs, both overexpressed in lung cancer.
- The specific roles of RBX1 and SAG in lung tumorigenesis and patient survival remain unclear.
Purpose of the Study:
- To investigate the differential roles of RBX1 and SAG in lung cancer.
- To determine the impact of SAG on KrasG12D-driven lung tumorigenesis and patient prognosis.
- To explore the therapeutic potential of targeting SAG-CRL E3 ligases.
Main Methods:
- Correlation analysis of SAG and RBX1 expression with patient survival and disease stage.
- Murine models of KrasG12D-driven lung cancer with and without Sag deletion.
- In vitro studies using lung cancer cell lines with SAG knockdown.
- Analysis of signaling pathways (NF-κB, mTOR) and tumor suppressor substrates.
- Pharmacological inhibition of CRL E3 ligases using MLN4924.
Main Results:
- SAG overexpression, unlike RBX1, significantly correlates with poor patient prognosis and advanced lung cancer.
- Sag deletion suppressed KrasG12D-induced lung tumorigenesis and prolonged murine survival.
- SAG knockdown in lung cancer cells inhibited growth, survival, inactivated NF-κB and mTOR pathways, and increased tumor suppressor levels (p21, p27, NOXA, BIM).
- MLN4924 treatment also inhibited lung tumor formation via similar pathway inactivation.
Conclusions:
- SAG acts as a Kras-cooperating oncogene promoting lung tumorigenesis.
- Targeting SAG-CRL E3 ligases presents a promising therapeutic strategy for Kras-driven lung cancers.
Related Concept Videos
02:38The Ras Gene
Ras is a...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:24Small GTPases - Ras and Rho
Three regulatory proteins control their activity:
02:23Abnormal Proliferation
01:07MAPK Signaling Cascades
01:22PI3K/mTOR/AKT Signaling Pathway