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Role of Stat3 in regulating p53 expression and function
Guilian Niu1, Kenneth L Wright, Yihong Ma
1Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Abstract:
Loss of p53 function by mutation is common in cancer. However, most natural p53 mutations occur at a late stage in tumor development, and many clinically detectable cancers have reduced p53 expression but no p53 mutations. It remains to be fully determined what mechanisms disable p53 during malignant initiation and in cancers without mutations that directly affect p53. We show here that oncogenic signaling pathways inhibit the p53 gene transcription rate through a mechanism involving Stat3, which binds to the p53 promoter in vitro and in vivo. Site-specific mutation of a Stat3 DNA-binding site in the p53 promoter partially abrogates Stat3-induced inhibition. Stat3 activity also influences p53 response genes and affects UV-induced cell growth arrest in normal cells. Furthermore, blocking Stat3 in cancer cells up-regulates expression of p53, leading to p53-mediated tumor cell apoptosis. As a point of convergence for many oncogenic signaling pathways, Stat3 is constitutively activated at high frequency in a wide diversity of cancers and is a promising molecular target for cancer therapy. Thus, repression of p53 expression by Stat3 is likely to have an important role in development of tumors, and targeting Stat3 represents a novel therapeutic approach for p53 reactivation in many cancers lacking p53 mutations.
Insights
Oncogenic signaling pathways inhibit tumor suppressor p53 transcription via Stat3. Blocking Stat3 reactivates p53, promoting cancer cell apoptosis and offering a novel therapeutic strategy for many cancers.
Area of Science:
- Molecular Biology
- Cancer Biology
- Signal Transduction
Background:
- Loss of p53 tumor suppressor function is critical in cancer development.
- Many cancers exhibit reduced p53 expression without direct p53 mutations, suggesting alternative inactivation mechanisms.
Purpose of the Study:
- To elucidate mechanisms that disable p53 during early cancer development.
- To investigate the role of Signal Transducer and Activator of Transcription 3 (Stat3) in p53 regulation.
- To explore Stat3 as a therapeutic target for p53 reactivation in cancer.
Main Methods:
- Investigated Stat3 binding to the p53 promoter in vitro and in vivo.
- Utilized site-specific mutations in the p53 promoter to assess Stat3 binding effects.
- Examined the impact of Stat3 inhibition on p53 expression and cancer cell apoptosis.
Main Results:
- Oncogenic signaling pathways, via Stat3, inhibit p53 gene transcription.
- Stat3 binds to the p53 promoter, and mutations in this site reduce Stat3-mediated inhibition.
- Blocking Stat3 in cancer cells restores p53 expression and induces apoptosis.
Conclusions:
- Stat3 acts as a key repressor of p53 expression in the context of oncogenic signaling.
- Stat3 is a promising therapeutic target for reactivating p53 in cancers lacking p53 mutations.
- Targeting Stat3 offers a novel strategy for cancer therapy by restoring tumor suppressor function.
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