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Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
Published on: June 6, 2017
Cell cycle-dependent degradation of the methyltransferase SETD3 attenuates cell proliferation and liver tumorigenesis
Xiaoqing Cheng1, Yuan Hao2, Wenjie Shu1
1From the Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072.
Abstract:
Histone modifications, including lysine methylation, are epigenetic marks that influence many biological pathways. Accordingly, many methyltransferases have critical roles in various biological processes, and their dysregulation is often associated with cancer. However, the biological functions and regulation of many methyltransferases are unclear. Here, we report that a human homolog of the methyltransferase SET (SU(var), enhancer of zeste, and trithorax) domain containing 3 (SETD3) is cell cycle-regulated; SETD3 protein levels peaked in S phase and were lowest in M phase. We found that the β-isoform of the tumor suppressor F-box and WD repeat domain containing 7 (FBXW7β) specifically mediates SETD3 degradation. Aligning the SETD3 sequence with those of well known FBXW7 substrates, we identified six potential non-canonical Cdc4 phosphodegrons (CPDs), and one of them, CPD1, is primarily phosphorylated by the kinase glycogen synthase kinase 3 (GSK3β), which is required for FBXW7β-mediated recognition and degradation. Moreover, depletion or inhibition of GSK3β or FBXW7β resulted in elevated SETD3 levels. Mutations of the phosphorylated residues in CPD1 of SETD3 abolished the interaction between FBXW7β and SETD3 and prevented SETD3 degradation. Our data further indicated that SETD3 levels positively correlated with cell proliferation of liver cancer cells and liver tumorigenesis in a xenograft mouse model, and that overexpression of FBXW7β counteracts the SETD3's tumorigenic role. We also show that SETD3 levels correlate with cancer malignancy, indicated by SETD3 levels that the 54 liver tumors are 2-fold higher than those in the relevant adjacent tissues. Collectively, these data elucidated that a GSK3β-FBXW7β-dependent mechanism controls SETD3 protein levels during the cell cycle and attenuates its oncogenic role in liver tumorigenesis.
Insights
A new study reveals a mechanism controlling SETD3 protein levels, crucial for liver cancer progression. This research identifies how glycogen synthase kinase 3 beta (GSK3β) and F-box and WD repeat domain containing 7 beta (FBXW7β) regulate SETD3, impacting cell proliferation and tumorigenesis.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Mechanisms
Background:
- Histone modifications, such as lysine methylation, are vital epigenetic marks influencing biological pathways.
- Dysregulation of methyltransferases, like SETD3, is frequently linked to cancer development.
- The precise biological functions and regulatory mechanisms of many methyltransferases remain incompletely understood.
Purpose of the Study:
- To investigate the cell cycle regulation of the human methyltransferase SETD3.
- To identify the specific E3 ubiquitin ligase responsible for SETD3 degradation.
- To elucidate the molecular mechanism controlling SETD3 protein levels and its role in liver tumorigenesis.
Main Methods:
- Analysis of SETD3 protein levels across the cell cycle.
- Identification of FBXW7β as the specific E3 ligase targeting SETD3 for degradation.
- Investigation of the role of glycogen synthase kinase 3 beta (GSK3β) in phosphorylating SETD3 for FBXW7β recognition.
- Mutation analysis of potential phosphodegron sites in SETD3.
- In vivo studies using a liver cancer xenograft mouse model.
Main Results:
- SETD3 protein levels exhibit cell cycle-dependent regulation, peaking in S phase and decreasing in M phase.
- The β-isoform of FBXW7 (FBXW7β) specifically mediates the degradation of SETD3.
- GSK3β phosphorylates a specific phosphodegron (CPD1) on SETD3, facilitating FBXW7β-mediated recognition and degradation.
- Depletion or inhibition of GSK3β or FBXW7β leads to increased SETD3 levels.
- Mutations in the CPD1 site of SETD3 abolish FBXW7β interaction and prevent degradation.
- Elevated SETD3 levels correlate with increased liver cancer cell proliferation and tumorigenesis in vivo.
- SETD3 levels are significantly higher in liver tumors compared to adjacent normal tissues, correlating with malignancy.
Conclusions:
- A novel GSK3β-FBXW7β-dependent pathway regulates SETD3 protein stability during the cell cycle.
- This regulatory mechanism attenuates the oncogenic function of SETD3 in liver tumorigenesis.
- Targeting this pathway may offer therapeutic strategies for liver cancer.
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