Ezh2 promotes TRβ lysine methylation-mediated degradation in hepatocellular carcinoma

Park Su Chan; Lee Ji Min

doi:10.1007/s13258-021-01196-8

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저자정보: Park Su Chan (Kangwon National University) Lee Ji Min (Kangwon National University)

저널정보: 한국유전학회 Genes & Genomics Genes & Genomics Vol.44 No.3

발행연도: 2022.3

수록면: 369 - 377 (9page)

DOI: 10.1007/s13258-021-01196-8

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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.

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.

#Post-translational modification · Thyroid hormone · Transcriptional regulator · Tumor suppressor · Metabolic homeostasis · Hepatocellular carcinoma

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Park Su Chan

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Lee Ji Min

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주요연구분야 자연과학 > 생물학 자연과학 > 화학

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