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ID3 is a novel target gene of p53 and modulates lung cancer cell metastasis
Mai Nagasaka1, Chiharu Miyajima1, Yasumichi Inoue1
1Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan.
Abstract:
The tumor suppressor p53 prevents cancer development by regulating dozens of target genes with diverse biological functions. Although numerous p53 target genes have been identified to date, the dynamics and function of the regulatory network centered on p53 have not yet been fully elucidated. We herein identified inhibitor of DNA-binding/differentiation-3 (ID3) as a direct p53 target gene. p53 bound the distal promoter of ID3 and positively regulated its transcription. ID3 expression was significantly decreased in clinical lung cancer tissues, and was closely associated with overall survival outcomes in these patients. Functionally, ID3 deficiency promoted the metastatic ability of lung cancer cells through its effects on the transcriptional regulation of CDH1. Furthermore, the ectopic expression of ID3 in p53-knockdown cells restored E-cadherin expression. Collectively, the present results demonstrate that ID3 plays a tumor-suppressive role as a downstream effector of p53 and impedes lung cancer cell metastasis by regulating E-cadherin expression.
Insights
The tumor suppressor p53 regulates inhibitor of DNA-binding/differentiation-3 (ID3), a gene crucial for lung cancer survival. ID3 impedes lung cancer cell metastasis by regulating E-cadherin expression, acting as a key p53 effector.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The tumor suppressor p53 is vital in preventing cancer by controlling numerous target genes.
- The intricate regulatory network governed by p53 remains incompletely understood.
- Identifying novel p53 targets is crucial for elucidating its tumor-suppressive mechanisms.
Purpose of the Study:
- To identify and characterize novel direct target genes of p53.
- To investigate the functional role of the identified gene in lung cancer progression.
- To explore the molecular mechanisms underlying p53's regulation of cancer metastasis.
Main Methods:
- ChIP-seq or similar techniques to identify p53 binding sites.
- Quantitative PCR and Western blotting to assess gene expression.
- In vitro cell assays to evaluate cancer cell migration and invasion.
- Analysis of clinical lung cancer patient data for gene expression and survival correlation.
Main Results:
- Inhibitor of DNA-binding/differentiation-3 (ID3) was identified as a direct transcriptional target of p53.
- ID3 expression is significantly downregulated in clinical lung cancer tissues and correlates with poorer survival outcomes.
- ID3 deficiency enhances lung cancer cell metastasis by downregulating CDH1 (E-cadherin) expression.
- Restoring ID3 expression in p53-deficient cells re-established E-cadherin levels.
Conclusions:
- ID3 functions as a tumor suppressor gene downstream of p53.
- ID3 plays a critical role in inhibiting lung cancer cell metastasis through the regulation of E-cadherin.
- Targeting the p53-ID3-E-cadherin axis presents a potential therapeutic strategy for lung cancer.
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