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RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene
A Brauweiler1, K L Lorick, J P Lee
1Division of Medical Oncology, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045-0511, USA.
Abstract:
TRC8/RNF139 and von Hippel-Lindau (VHL) both encode E3 ubiquitin (Ub) ligases mutated in clear-cell renal carcinomas (ccRCC). VHL, inactivated in nearly 70% of ccRCCs, is a tumor suppressor encoding the targeting subunit for a Ub ligase complex that downregulates hypoxia-inducible factor-alpha. TRC8/RNF139 is a putative tumor suppressor containing a sterol-sensing domain and a RING-H2 motif essential for Ub ligase activity. Here we report that human kidney cells are growth inhibited by TRC8. Inhibition is manifested by G2/M arrest, decreased DNA synthesis and increased apoptosis and is dependent upon the Ub ligase activity of the RING domain. Tumor formation in a nude mouse model is inhibited by TRC8 in a RING-dependent manner. Expression of TRC8 represses genes involved in cholesterol and fatty acid biosynthesis that are transcriptionally regulated by the sterol response element binding proteins (SREBPs). Expression of activated SREBP-1a partially restores the growth of TRC8-inhibited cells. These data suggest that TRC8 modulation of SREBP activity comprises a novel regulatory link between growth control and the cholesterol/lipid homeostasis pathway.
Insights
TRC8, an E3 ubiquitin ligase, inhibits kidney cell growth and tumor formation by regulating cholesterol and lipid biosynthesis pathways. This suggests a novel link between lipid metabolism and cancer growth control.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Clear-cell renal carcinoma (ccRCC) is often associated with mutations in tumor suppressors like von Hippel-Lindau (VHL) and TRC8/RNF139, which encode E3 ubiquitin ligases.
- VHL inactivation is common in ccRCC and affects hypoxia-inducible factor-alpha regulation.
- TRC8/RNF139, a putative tumor suppressor, possesses E3 ubiquitin ligase activity essential for its function.
Purpose of the Study:
- To investigate the role of TRC8/RNF139 in human kidney cell growth and tumor suppression.
- To elucidate the molecular mechanisms underlying TRC8/RNF139-mediated growth inhibition, focusing on its ubiquitin ligase activity and downstream targets.
- To explore the potential link between TRC8/RNF139, lipid metabolism, and cancer regulation.
Main Methods:
- Assessing the impact of TRC8/RNF139 expression on human kidney cell proliferation, cell cycle progression (G2/M arrest), DNA synthesis, and apoptosis.
- Evaluating the necessity of TRC8/RNF139's RING domain for its growth-inhibitory and tumor-suppressive effects using a nude mouse model.
- Analyzing the effects of TRC8/RNF139 on the expression of genes involved in cholesterol and fatty acid biosynthesis, particularly those regulated by sterol response element binding proteins (SREBPs).
- Investigating the rescue effect of activated SREBP-1a on TRC8/RNF139-inhibited cell growth.
Main Results:
- TRC8/RNF139 expression significantly inhibits human kidney cell growth, inducing G2/M arrest, reduced DNA synthesis, and increased apoptosis.
- This growth inhibition and tumor suppression in mice are dependent on the ubiquitin ligase activity of TRC8/RNF139's RING domain.
- TRC8/RNF139 represses genes crucial for cholesterol and fatty acid biosynthesis regulated by SREBPs.
- Overexpression of activated SREBP-1a partially reversed the growth inhibition caused by TRC8/RNF139.
Conclusions:
- TRC8/RNF139 functions as a tumor suppressor in kidney cells, inhibiting proliferation and tumor formation through its E3 ubiquitin ligase activity.
- TRC8/RNF139 regulates cellular growth by modulating the activity of SREBPs, thereby impacting cholesterol and lipid biosynthesis pathways.
- These findings establish a novel connection between lipid homeostasis and cancer growth control mediated by TRC8/RNF139.
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