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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
ECRG2, a novel transcriptional target of p53, modulates cancer cell sensitivity to DNA damage
Harsh Patel1, M Saeed Sheikh1, Ying Huang2
1Department of Pharmacology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA.
Abstract:
Esophageal Cancer-Related Gene 2 (ECRG2) is a recently identified tumor suppressor, its regulation and involvement in DNA damage response are unknown. Here, we show that DNA damage-induced ECRG2 upregulation coincided with p53 activation and occurred in a p53-dependent manner. We identified two p53-binding sites within ECRG2 promoter and found the promoter activity, mRNA, and protein expression to be regulated by p53. We show that DNA damage significantly enhanced p53 binding to ECRG2 promoter at the anticipated p53-binding sites. We identified a novel natural ECRG2 promoter variant harboring a small deletion that exists in the genomes of ~38.5% of world population and showed this variant to be defective in responding to p53 and DNA-damage. ECRG2 overexpression induced cancer cell death; ECRG2 gene disruption enhanced cell survival following anticancer drug treatments even when p53 was induced. We showed that lower expression of ECRG2 in multiple human malignancies correlated with reduced disease-free survival in patients. Collectively, our novel findings indicate that ECRG2 is an important target of p53 during DNA damage-induced response and plays a critical role in influencing cancer cell sensitivity to DNA damage-inducing cancer therapeutics.
Insights
Esophageal Cancer-Related Gene 2 (ECRG2) is upregulated by p53 during DNA damage. A common ECRG2 variant impairs this response, affecting cancer cell survival and patient prognosis.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Esophageal Cancer-Related Gene 2 (ECRG2) is a novel tumor suppressor.
- Its regulation and role in DNA damage response remain uncharacterized.
Purpose of the Study:
- To elucidate the regulation of ECRG2 by p53 during DNA damage.
- To investigate the functional impact of ECRG2 in cancer cell response to DNA damage and its clinical relevance.
Main Methods:
- p53-binding site analysis in the ECRG2 promoter.
- Reporter assays to assess promoter activity.
- mRNA and protein expression analysis following DNA damage.
- CRISPR/Cas9 gene editing for ECRG2 disruption.
- Analysis of ECRG2 expression in human malignancies.
Main Results:
- DNA damage induces ECRG2 upregulation in a p53-dependent manner, with p53 binding to specific sites on the ECRG2 promoter.
- A prevalent ECRG2 promoter variant with a deletion is unresponsive to p53 and DNA damage.
- ECRG2 overexpression promotes cancer cell death, while its disruption enhances cell survival under genotoxic stress.
- Reduced ECRG2 expression correlates with poorer disease-free survival in cancer patients.
Conclusions:
- ECRG2 is a direct p53 target gene crucial for the DNA damage response.
- The identified ECRG2 promoter variant compromises tumor suppression and impacts therapeutic sensitivity.
- ECRG2 functions as a key determinant of cancer cell fate following DNA damage, influencing patient outcomes.
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