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Ezh2 promotes TRβ lysine methylation-mediated degradation in hepatocellular carcinoma
1Department of Molecular Bioscience, College of Biomedical Sciences, Kangwon National University, Chuncheon, 24341, Korea.
Background:
Post-translational modification (PTM) of proteins controls various cellular functions of transcriptional regulators and participates in diverse signal transduction pathways in cancer. The thyroid hormone (triiodothyronine, T3) plays a critical role in metabolic homeostasis via its direct interaction with the thyroid hormone receptor beta (TRβ). TRβ is involved in physiological processes, such as cell growth, differentiation, apoptosis, and maintenance of metabolic homeostasis through transcriptional regulation of target genes.
Objective:
This study was performed to characterize the specific PTM of TRβ is an active control mechanism for the proteasomal degradation of TRβ in transcriptional signaling pathways in hepatocellular carcinoma cells.
Methods:
Based on a previous study, we predicted that the lysine methyltransferase and methylation sites of TRβ by comparing the amino acid sequences of histone H3 and TRβ. Methyl-acceptor site of TRβ was confirmed by point mutation. TRβ protein stability was evaluated by ubiquitination assay with MG132. For glucose starvation, HepG2 cells were incubated in media without D-glucose. Proliferation-related proteins were detected by western blotting. MicroRNA level and autophagy marker were measured by real-time qPCR.
Results:
The presence of enhancer of zeste homolog 2 (Ezh2), a methyltransferase of H3 lysine 27, as a methyltransferase of TRβ also revealed that direct lysine methylation and consequent stimulated protein degradation of TRβ underlies the negative correlation between Ezh2 and TRβ. Notably, glucose starvation significantly increased lysine methylation, and methylated TRβ showed further protein instability leading to an increase in the proliferation and growth of hepatocellular carcinoma cells.
Conclusions:
TRβ functions as a tumor suppressor in various cancers; therefore, we evaluated the effect of TRβ degradation on oncogenesis during glucose starvation. These data clearly define a functional model and provide a link between metabolism and cancer by regulating methyl-dependent protein levels of tumor suppressors. Taken together, maintaining TRβ against methyl-dependent degradation is considered a possible therapeutic target for cancer progression.
Insights
Thyroid hormone receptor beta (TRβ) protein is degraded via lysine methylation, especially during glucose starvation. This TRβ degradation promotes hepatocellular carcinoma cell growth, suggesting TRβ stabilization as a potential cancer therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Endocrinology
Background:
- Post-translational modifications (PTMs) regulate protein function in cellular signaling and cancer.
- Thyroid hormone (T3) interacts with thyroid hormone receptor beta (TRβ), crucial for metabolic homeostasis and cell growth.
- TRβ acts as a transcriptional regulator involved in cell growth, differentiation, apoptosis, and metabolism.
Purpose of the Study:
- To investigate the specific PTM of TRβ as a control mechanism for its proteasomal degradation.
- To understand the role of TRβ degradation in hepatocellular carcinoma (HCC) signaling pathways.
- To link metabolic changes to cancer progression via TRβ regulation.
Main Methods:
- Predicted TRβ methylation sites by comparing amino acid sequences with histone H3.
- Confirmed TRβ methyl-acceptor sites using point mutation.
- Assessed TRβ protein stability via ubiquitination assays and MG132 treatment.
- Investigated TRβ changes under glucose starvation in HepG2 cells.
- Analyzed proliferation-related proteins, microRNA levels, and autophagy markers.
Main Results:
- Identified enhancer of zeste homolog 2 (Ezh2) as a TRβ methyltransferase.
- Demonstrated that Ezh2-mediated lysine methylation directly stimulates TRβ degradation, showing a negative correlation between Ezh2 and TRβ levels.
- Observed that glucose starvation significantly increases TRβ lysine methylation and protein instability.
- Found that increased TRβ degradation under glucose starvation correlates with enhanced HCC cell proliferation and growth.
Conclusions:
- TRβ functions as a tumor suppressor in cancer.
- TRβ degradation, enhanced by lysine methylation during glucose starvation, promotes oncogenesis.
- A functional model linking metabolism and cancer through methyl-dependent regulation of tumor suppressor protein levels is established.
- Stabilizing TRβ against methyl-dependent degradation presents a potential therapeutic strategy for cancer progression.
